Juillet 2019

Vendredi 19 Juillet – 11:00 – Salle des Conférences – Médiathèque Paul Zech

Jyoti Jaiswal

Children’s National Medical Center, Georges Washington University, Washington DC

Beyond the energy needs –
what can diseases tell us about the role of mitochondria in muscle repair

Invité par Benedicte Chazaud

Abstract

Skeletal muscle relies on mitochondria to produce energy needed for its contractility. Muscle mitochondria are also signaling hubs that regulate structural and functional changes in the muscle in response to physical activity. However, all the mechanical load and activity can cause sarcolemmal tear which impacts on muscle function in many muscle diseases. We have identified that a novel role of mitochondria in the muscle is to facilitate repair of such sarcolemmal injuries and defect in this contributes to muscle diseases. Therefore, to develop therapies that can improve sarcolemmal integrity in muscular dystrophies, there is an unmet need to better understand the underlying mechanism. I will discuss our effort that led to the identification of this new role of mitochondria, and what we have learned since about this mechanism by way of muscle diseases linked to mitochondrial deficiency in handling calcium, membrane potential, and its dynamics.
If you wish to meet Jyoti Jaiswal, please contact Bénédicte Chazaud (benedicte.chazaud@inserm.fr).

Vendredi 12 Juillet – 11:00 – Salle des Conférences – Médiathèque Paul Zech

Alban DE KERCHOV D’EXAERDE

ULB Neuroscience Institute, Lab of Neurophysiology, Bruxelles

Neuronal populations and genes involved in drug addiction

Invité par Laurent Schaeffer

Abstract

Motivational processes are under the critical influence of the ventral part of basal ganglia, comprising several interconnected nuclei (as striatum, globus pallidus and ventral tegmental area (VTA)). Addictive drugs increase extracellular DA levels in the ventral striatum, Nucleus Accumbens (NAc), and share this ability despite varied pharmacological properties and mechanisms of action. A major goal in the field of drug addiction has been to uncover the molecular mechanisms underlying addiction-associated neuroadaptations. It has been hypothesized that one such mechanism is the regulation of gene expression7, and there have been numerous studies that have documented altered expression of genes in the NAc. We discovered that Maged1 (Melanoma antigen genes d1) has a mandatory role in behaviours related to drug addiction in BG. Mice lacking Maged1 are insensitive to the behavioural effects of cocaine as assessed by locomotor sensitization, conditioned place preference (CPP), and drug self-administration. Electrophysiological experiments in brain slices and conditional KO mice demonstrated that Maged1 is critical for cortico-accumbal neurotransmission. Further, expression of Maged1 in the prefrontal cortex and amygdala, but not in dopaminergic or striatal neurons, is required for cocaine-induced extracellular DA release in the NAc as well as cocaine-mediated behavioural sensitization and acute cocaine effect respectively. This work identifies Maged1 as a critical molecule involved in cellular processes in BG and behavioural models of addiction.
I initially learned molecular biology and biochemistry during my PhD to decipher the role plasma membrane H+-ATPase in yeast and plant (P.I. Pr André Goffeau). Next, I learned molecular neurobiology, mouse transgenesis, single cell PCR by working on the physiology of nAChRs in NMJ and in catecholaminergic neurons during my postdoctoral fellowship at Pasteur Institute in Paris (P.I. Pr Jean-Pierre Changeux). For the past 16 years, my main interest is the study of the roles of neuronal populations and genes in pathophysiology of Basal Ganglia (BG), mainly in neuropsychiatric models and in the striatum. Our program is based on our ability to target and manipulate genetically and specifically the two populations of Striatal Projecting Neurons (SPN) to evaluate their contributions or the contribution of specific genes in SPNs in various behaviors. My group was the first to demonstrate in vivo that the SPNs of the indirect pathway of BG has an inhibitory effect on locomotion and drug preference and are necessary for drug sensitization and cataleptic effect of antipsychotic by a proper genetic targeting of this population. I am currently Research Director at FRS-FNRS in Belgium at Brussels and President-Elect of the Belgian Society of Neuroscience.

Vendredi 5 Juillet – 11:00 – Amphi 3

Virginie MOURNETAS

ISTEM Paris

Duchenne muscular dystrophy, a developmental disease

Invitée par Laurent Schaeffer

Abstract

Duchenne muscular dystrophy (DMD) is a recessive X-linked monogenic myopathy. Mutations in the dystrophin gene result in a progressive, yet severe muscle wasting as death occurs around 30. DMD boys are currently diagnosed around 4 – an age at which muscles have already suffered. Moreover, no treatment can currently stop this disease and efficacy of developing human therapies aiming at restoring the expression of dystrophin stays too low.
Our group has identified Dp412e, an embryonic isoform of dystrophin, leading us to investigate DMD during skeletal muscle development by modelling it with human induced pluripotent stem cells (hiPSCs). Our multi-omics study of the differentiation dynamics strongly argues for an early developmental manifestation of DMD whose onset is triggered before the entry into the skeletal muscle compartment, where mitochondria play an initial role and fibrosis is an intrinsic cell feature of skeletal muscle cells. It also demonstrates that hiPSCs 1) recapitulate key developmental steps, enabling the identification of early disease markers; 2) are suitable for studying skeletal myogenesis in human, in both healthy and disease contexts; and 3) are compatible with high-throughput experiments, thus increasing the capability of drug screening.

 


Juin 2019

Vendredi 28 Juin – 11:00 – Médiathèque Paul Zech

Thomas PREAT

ESPCI Paris-CNRS

Energy metabolism shapes Drosophilia long-term memory

Invité par Jean-Louis Bessereau

Abstract

Understanding the links between neuronal plasticity which underlies memory and energy metabolism is a major goal of brain studies. The brain is a main energy consumer and the central regulator of energy homeostasis, and it prioritizes its own supply over peripheral organs. However we have shown in Drosophila that the brain is also able to regulate its own activity under energy shortage to favor survival. I will describe how our integrated strategy to study at the molecular, circuit and behavioral levels how the brain energy status is transmitted to the drosophila olfactory memory center, and how this information is used to regulate long-term memory formation. Finally, I will present recent data linking sexual activity with memory capacity.

 


Mai 2019

Mercredi 22 Mai – 11:00 – Amphi 3

Luc BERTRAND

Université catholique de Louvain, Brussels

AMPK in cardiac pathologies, not just a metabolic sensor !

Abstract
The AMP-activated protein kinase (AMPK) has been firstly discovered to be activated under metabolic stress conditions such as myocardial ischemia. Its protective action during an ischemic episode has been demonstrated by several research groups. By targeting metabolism, AMPK helps the heart to survive under such deleterious conditions. However, AMPK action extends beyond metabolism and acute stress conditions. Indeed, it has been more recently shown that AMPK acts as protector of the heart in several chronic diseases such heart failure, diabetic cardiomyopathy and cardiac hypertrophy by acting in cardiomyocytes but also on the other cell types such as fibroblasts. Very recently, our group discovered a connection between AMPK and a particular post-translational modification called O-GlcNAcylation, this interplay acting a major role in the development of cardiac hypertrophy. The lecture will focus on the different protective roles of cardiac AMPK.


Vendredi 24 Mai – 11:00 – Salle Hermann

Michisuke Yuzaki

Keio University School of Medicine, Tokyo

Bridge over troubled synapses — a new synthetic synapse organizer

Invité par Jean-Louis Bessereau

Abstract
Synaptic organizers regulate formation, elimination and maintenance of synaptic connections throughout life. Although excitatory and inhibitory synaptic imbalance underlies certain neuropsychiatric and neurological disorders, no tools are currently available to directly modulate the balance. Recently, a new class of synaptic organizers, termed extracellular scaffolding proteins (ESPs), are reported to acutely and potently modulate specific synapses by directly binding to certain pre- and postsynaptic membrane proteins. Here, to expand the repertoire of ESPs with a variety of pre- and postsynaptic specificities, we developed a new synthetic ESP, Cbln1–neuronal pentraxin 1 (NP1) chimera (CPTX), by exploiting the structure of NP1 and Cbln1. Unlike original Cbln1, CPTX induced excitatory synapses by recruiting AMPA glutamate receptors in vitro. Furthermore, CPTX restored excitatory synapses and synaptic plasticity in vivo, as well as spatial and contextual memories in Alzheimer’s disease model mice. In this talk, I would like to discuss a possible toolkit of ESPs with a variety of pre- and postsynaptic specificities to modify neuronal circuits.


Lundi 13 Mai- 11:00 – Amphi 4

Marc HAMMARLUND

Yale University, New Haven, USA

How C. elegans neurons sense and respond to injury

Invité par Jean-Louis Bessereau

Abstract
The nervous system has an extraordinary capacity to repair damage by regenerating axons and synaptic connections. I will discuss the molecular and cellular basis of axon regeneration in C. elegans, and describe how regenerated synapses and circuits differ from those generated during development. Finally, I will present new data on a novel ncRNA pathway that controls regeneration.


Mars 2019

Lundi 25 Mars à 14:00 – Salle Hermann

Saadi Khochbin

Institute for Advanced Biosciences, La Tronche, France

Les séminaires du Chromatin Club – Metabolism-driven epigenetics

Invité par Armelle Corpet / Patrick Lomonte

Annonce de séminaire


Février 2019

Vendredi 1 Février à 11:00 – Amphi 2bis

Frédéric RELAIX

INSERM – IMRB U955-E10, F-94010 Créteil, France

PAX3 controls the adaptive response of skeletal muscle stem cells to environmental stress

Invité par Rémi Mounier

Abstract
We have identified a molecular link between the Aryl hydrocarbon Receptor (AhR) environmental stress pathway and Pax3/Pax7 developmental genes during craniofacial development. Since Pax3/7 are key regulators of muscle stem cells (muscle satellite cells), we investigated the cellular and molecular impact of chronic 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) exposure on skeletal muscle and satellite cells in the adult. We combined in vivo and ex vivo approaches, in order to analyse the impact of chronic exposure to TCDD in several muscles such as tibialis anterior and biceps brachii. While all MuSCs express the transcription factor PAX7, we show that a muscle-specific subset also express PAX3 and exhibit resistance to environmental stress. Upon systemic TCDD treatment, PAX3-negative MuSCs display impaired survival, atypical activation and sporadic differentiation through the xenobiotic Aryl Hydrocarbon Receptor. We further show PAX3-positive MuSCs become sensitized to environmental stress when PAX3 function is impaired and that PAX3-mediated induction of mTORC1-dependent G(alert) is required for protection. Our study therefore identifies a functional heterogeneity of MuSCs in response to environmental stress controlled by PAX3.

Annonce de séminaire


Janvier 2019

Vendredi 25 Janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Nicolas RENIER

ICM – Institut du Cerveau et de la Moelle Epinière Paris – FRANCE

A framework for the study of behaviour and plasticity in the adult brain using light sheet microscopy

Invité par Julien Courchet

Abstract
There has been over the past 6 years a convergence in the fields of optics, biochemistry and computing leading to dramatic improvements in light sheet microscopy, tissue clearing protocols and image analysis algorithms. The convergence of these different fields has the potential to streamline brain studies by accelerating data acquisition speed and reliability over the current whole brain analysis pipelines based on serial sectioning methods. We previously developed the iDISCO+ protocol for immunostaining and imaging intact adult mouse brains. As a companion tool, we also developed and distribute ClearMap, an open source environment to segment objects and map them onto reference atlases optimized for large 3D datasets. We used this pipeline as a discovery tool to find brain regions active in correlation with various behaviors by mapping neuronal activity landscapes derived from Fos expression. Here, I will present recent unpublished projects made possible by our upcoming brain mapping pipeline ClearMap 2, expanding the repertoire of applications derived from intact whole brain preparations. We hope that ongoing developments in light sheet microscopy and image analysis pipelines will facilitate our understanding of individual variations in brain activity, connectivity and structure.

Annonce de séminaire


Novembre 2018

Vendredi 30 November à 11:00 – Salle des Pas Perdus – 1er étage – Faculté de Médecine Lyon Est

Hugues NURY

Institut de Biologie Structurale, Grenoble

Structures and transitions of the serotonin 5-HT3 receptor

Invité par Thomas Boulin

Abstract
The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel. It belongs to a large family of receptors that transduce signals across the plasma membrane​: upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions, which result in transient opening of a pore permeable ​to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression. I will present structures of the 5-HT3 receptor obtained by crystallography or cryo-electron microscopy. The structures, obtained in complex with inhibitors or agonists, represent snapshots in different states: inhibited, pre-active, active. Together with molecular dynamics simulations and functional recordings, they reveal the molecular mechanism of the fast neurotransmission mediated by 5HT3 receptors.

Annonce de séminaire


Vendredi 30 Novembre à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est

Emmanuel COMPE

Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch, Strasbourg

TFIIH and TFIIE mutations: when transcriptional deficiencies lead to neurological disorders

Invité par Ambra Giglia-Mari

Abstract
Trichothiodystrophy (TTD) is an autosomal recessive disorder mainly related to mutations in the DNA repair/transcription factor TFIIH. In addition to the typical dry and brittle hair, individuals with TTD develop neurological defects, including microcephaly and hypomyelination. Using a TTD transgenic mouse model, we previously observed a spatial and selective deregulation of thyroid hormone target genes in the brain, suggesting that transcriptional failures contribute to TTD phenotypes.
Remarkably, mutations within TFIIE, another general transcription factor, have been recently associated with TTD. Such observation prompted us to accurately dissect the partnerships occurring between TFIIE and TFIIH during transcription. Our work revealed an unexpected dynamic process during which TFIIE act as key factors to recruit and position the kinase module of TFIIH within the preinitiation complex. Strikingly, TTD-related mutations in either TFIIH or TFIIE similarly disrupt this early transcriptional process, which could explain why alterations in different transcription factors can lead to the same clinical syndrome.

Annonce de séminaire


Vendredi 16 Novembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Laurent BARTHOLIN

CRCL, Lyon

The obnoxious faces of TGFbeta in pancreatic cancer

Invité par Rémi Mounier

Abstract
The Transforming growth factor beta (TGFB) is a pleiotropic secreted factor with many roles during embryonic and adult life. In cancer, it behaves either as a tumor suppressor or a tumor promoter. To understand this functional duality, our lab have been using as a model Pancreatic Ductal Adenocarcinoma (PDAC), one of the most aggressive tumor, which is expected to become the second cancer-related cause of death by 2030 (after lung cancer). Our work is focused on the oncogenic properties of TGFB with the final goal to specifically target them by developing innovating therapeutics. During this presentation, I will present our work to understand the TGFB oncogenic effects at the molecular (a “new” oncogenic signaling pathway), cellular (effect on differentiation of pancreatic acinar cells), organ (interaction between PDAC cells and nerves invading the tumor) and whole body levels (interaction with muscle).


Décembre 2018

Vendredi 14 Décembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Fabien LE GRAND

Centre de Recherche en Myologie, Paris

Signaling pathways in muscle tissue regeneration

Invité par Laurent Schaeffer

Abstract
The development and repair of complex metazoan tissues are coordinated by a startlingly small number of evolutionarily conserved signaling pathways. These signals can act in parallel but often function as an integrated hyper-network. Our research aims at understanding the signaling nodes defining this molecular circuitry and the biological significance of pathway cross-talk, using skeletal muscle as a fitting model. Regeneration of the adult muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). We previously demonstrated that numerous WNT molecules are secreted in the local milieu during muscle regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP (1). To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific mutations (2, 3). Mechanistically, we observed that Wnt/ß-catenin signaling orchestrate the cytoplasmic relocalisation of the H3K9 methyltransferase SETDB1 during differentiation (4). We further investigated how Wnt/ß-catenin signaling is connected to Bone morphogenetic protein (BMP) and Transforming growth factor beta (TGF-ß) pathways. Recent work in our lab consisted in dissecting the impact on these pathways on MuSC return to the niche and fusion, respectively. Nevertheless, our understanding of the cells that compose skeletal muscle tissue is limited and molecular definitions of the principal cell types are lacking. This hinders our capacity to decipher signal integration and reciprocity between cells. We thus used a novel combined approach of single-cell RNA-sequencing and mass cytometry and precisely mapped 10 different cell types in adult mouse skeletal muscle, including two previously unidentified populations (5). This cartography yields crucial insights into muscle-resident cell type identities and will be exploited to build a muscle connectome.


Mercredi 19 Décembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Bert Blaauw

Venetian Insitute of Molecular Medicine

The role of mTORC1 signaling in adult skeletal muscle

Invité par Laurent Schaeffer

Abstract
It is well established that mTORC1 signaling is key modulator of skeletal muscle mass and function. Surprisingly, despite the fact that skeletal muscle undergoes major changes in size and contractility in numerous diseases, no genetic loss-of-function model has been generated to determine the effect of inducible deletion of mTORC1 in adult skeletal muscle. Here we generated inducible, muscle-specific Raptor and mTOR k.o. mice. Interestingly, we do not observe a change in muscle size or contractile properties one month after deletion. However, treating these mice with the mTOR-inhibitor rapamycin is sufficient to induce a very rapid and marked myopathy, suggesting that little residual mTOR signaling can maintain muscle homeostasis in adult muscle. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by muscle dysfunction, regeneration, glycogen accumulation and mitochondrial dysfunction and block in autophagy. Unexpectedly, one of the best markers of reduced mTOR signaling in muscle fibers is the appearance of denervated fibers. Both muscle-specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce the appearance of numerous NCAM-positive fibers, muscle fibrillation, and neuromuscular junction fragmentation. Taken together, these results link one of the most important anabolic pathways in skeletal muscle fibers to the maintenance of the NMJ.


Octobre 2018

Mardi 9 Octobre à 11:00 – Salle RBC 301

Hélène PUCCIO

Department of Translational Medecine and Neurogenetics, IGBMC, Strasbourg

Advances in Friedreich Ataxia: understanding the function of frataxin and developing therapeutic approaches

Invité par Laurent Schaeffer

Abstract
Friedreich’s ataxia (FA), the most common autosomal recessive ataxia, is characterized by a sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy and increase incidence of diabetes. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Fe-S clusters are ancient and essential cofactors that participate in a number of cellular processes ranging from mitochondrial respiration to DNA metabolism. In eukaryotes, de novo Fe-S biogenesis takes place within mitochondria and relies on proteins that are highly conserved from bacteria to humans. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in individuals with FA. To date, no treatment exists for stopping or slowing FA disease.
Over the past years, we have generated cellular and mouse models that reproduce important progressive pathological and biochemical features of the human disease, including cardiac hypertrophy, mixed cerebellar and sensory ataxia, Fe-S enzyme deficiency, and intramitochondrial iron accumulation. These models have enabled us to demonstrate that Fe-S deficit is a primary event of the disease leading to iron metabolism deregulation through the activation of the iron-regulatory protein, IRP1. These models are excellent models for deciphering the physiopathology of the disease and for testing pre-clinical therapeutic protocols. The latest advances in understanding the pathophysiology will be discussed, with a particular emphasis on new neurological models that are being developed as well as therapeutic approaches.


Mercredi 10 Octobre à 14:00 – Salle des Pas Perdus – 1er étage – Faculté de Médecine Lyon Est

Juliette GODIN

Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg

Pleiotropic activities of the (atypical ?) kinesin KIF21B during cortical development

Invité par Julien Courchet

Abstract
Cortical development progresses through concurrent steps, including neural proliferation, migration and differentiation, that rely on dynamic cell shape remodeling which largely depends on the tight regulation of the microtubules (MT) cytoskeleton. Mutations in tubulin, MT associated proteins or motors have been linked to several neurodevelopmental disorders including malformation of cortical development (MCDs), affecting 2,5% of the world population. Here we identified KIF21B gene as a major locus of human neurodevelopmental disorder. We identified 4 de novo variants in KIF21B gene in patients with intellectual disabilities associated with several brain malformations, including microcephaly, corpus callosum agenesis or facial dimorphism. In support of the pathogenic potential of the discovered alleles, expression of KIF21B variant in mice using in utero electroporation or in zebrafish embryos recapitulated key neurodevelopmental phenotypes, namely migration and microcephaly. In addition, longitudinal neuroanatomical analysis of Kif21b KO model showed strong morphological defects starting prenatally and worsening with time. Finally, we demonstrated that Kif21b regulates migration of projection neurons through the tight control of locomotion and neural shape. Although its motility is dispensable, the regulatory function cytoskeleton dynamics is essential for neuronal migration. Altogether, our data represent an important step to delineate the mechanisms involving KIF21B-mediated MT dynamics and trafficking in the context of brain development.

Annonce de séminaire


Jeudi 11 Octobre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Belinda COWLING

Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg

Myostatin – A novel biomarker for Dnm2 therapy in Myotubular Myopathy mice

Invité par Vincent Gache

Abstract
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, myotubular myopathy (X-linked CNM), is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We have shown that antisense oligonucleotide (ASO) mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1 in mice, providing an attractive therapeutic strategy for this disease. We are now investigating blood-based biomarkers that can be used to monitor disease state and rescue in myotubular myopathy mice. Myostatin is a protein produced and released by myocytes, which acts in an autocrine function to inhibit muscle growth and differentiation. Our results suggest myostatin pathway is ‘turned down’ at the mRNA level in muscle biopsies, leading to low levels of circulating and endogenous muscle myostatin in plasma. We have generated preliminary data suggesting ASO-mediated DNM2 reduction results in an increase in circulating myostatin. With clinical trials for myotubular myopathy currently in progress, identification of novel blood-based biomarkers such as myostatin may allow for monitoring of treatment efficacy in patients.

Annonce de séminaire


Vendredi 12 Octobre à 11:00 – Salle Hermann – 1er étage – Faculté de Médecine Lyon Est

Luisa COCHELLA

Research Institute of Molecular Pathology (IMP), Vienna, Austria

Roles of micro RNAs in animal development: lessons from C.elegans

Invité par Florence Solari

Abstract
One of the main goals of developmental biology is to understand how the different cell types that constitute a multicellular organism are specified during its development. Luisa Cochella is a young PI (awarded for both ERC starting Grant and EMBO Young investigator program) who is currently exploring the different mechanisms of gene expression regulation that control this process. Her lab investigates how the transcriptional history of a cell influences its fate as well as how post- transcriptional mechanisms contribute to the diversification of the genetic programs that control cell fate. Luisa is more specifically interested in both neuronal and muscle differentiation

Annonce de séminaire


Mardi 30 Octobre à 11:00 – Salle Hermann – 1er étage – Faculté de Médecine Lyon Est

Huating WANG

The Chinese University of Hong Kong, Hong Kong, China

Functional investigation of LncRNAs and enhancers in skeletal muscle stem cells

Invité par Bénédicte Chazaud

Abstract
Previously, the majority of the human genome was thought to be « junk » DNA with no functional purpose. Over the past decade, evidence from numerous high-throughput genomic platforms reveals that even though less than 2% of the mammalian genome encodes proteins, a significant fraction can be transcribed into different complex families of non-coding RNAs (ncRNAs). Growing evidence supports that ncRNAs have fundamental roles as regulators of genomic output. Among various types of ncRNAs, microRNAs have dominated the current literature. Other groups, however, such as long ncRNAs (lncRNAs, >200nt), have been largely under explored.
Huating Wang’s lab is currently interested in studying the functional roles of long non-coding RNAs (lncRNAs and enhancers) in regulating gene expression in skeletal muscle stem cells and muscle regeneration.

Annonce de séminaire


Septembre 2018

Mardi 11 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Sonia Garel

Institut de Biologie de l’École Normale Supérieure, Paris

Microglia and prenatal inflammation in early cortical wiring

Invité par Jean-Louis Bessereau

Abstract

Prenatal inflammation and dysfunction of microglia, the brain resident macrophages, have both been associated with the etiology of several neuropsychiatric disorders, including schizophrenia and autism spectrum disorders. Consistently, microglia were shown to regulate neurogenesis, synaptic remodeling and maturation at postnatal stages. However, microglia invade the brain during mid-embryogenesis and could thus exert earlier prenatal and perinatal roles during normal and pathological brain wiring. Here we show that embryonic microglia, which display a transient uneven distribution, regulate the wiring of forebrain circuits. By taking advantage of multiple mouse models, including cell-depletion approaches, we found that perturbing microglia activity affects the development of neocortical inhibitory interneurons, which constitute main actors in neuropsychiatric diseases. In particular, absence, prenatal inflammation or functional perturbation of microglia affects the timely positioning of specific subsets of interneurons as well as their subsequent functional integration in the neocortex. We furthermore found that responses of microglia to environmental signals, including the ones from the microbiome, are sexually dimorphic in males and females. This remarkable finding has major implications for our comprehension of sexual biases in the occurrence of microglia-related diseases, such as the prevalence in males of neurodevelopmental disorders. Our work reveals key roles for immune cells during the normal assembly of cortical circuits and provides novel insights onto how microglia dysfunction or immune risks lead to pathological brain wiring.

Annonce de séminaire


Mercredi 19 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Yasushi Okamura

Graduate School of Medicine, Osaka University Suita

Coupling from electric signal to lipid signal; voltage-sensing phosphoinositide phosphatase

Invité par Vincent Jacquemond

Résumé

Biological membranes have dual roles in cell signaling: insulator for electrical signal by transfer of ion across membrane as well as the place for metabolism for production of lipid mediators such as arachidonic acids or phosphophositides. These two signals interact with each other through changes of ion concentration, mainly intracellular calcium ions, by the concerted activities of ion channels, transporters and GPCRs. There is a rare case where single membrane proteins directly link between electrical signal and lipid-mediated cell signaling. Voltage-sensing phosphatase consists of the ion channel like voltage sensor and PTEN-like phosphoinositide enzyme. In VSP, single voltage sensor regulates the downstream enzyme and the phosphoinositide phosphatase activity is activated by membrane depolarization leading to depletion of mainly PI(4,5)P2. Substrate specificity of VSP is more broad than PTEN; VSP shows both of 3-phosphatase activity and 5-phosphatase activity unlike PTEN which shows the rigid selectivity toward 3-phosphate of the inositol ring of PI(3,4,5)P3 and PI(3,4)P2. However, the key question how transmembrane voltage sensor regulates the cytoplasmic enzyme has remained unanswered, mainly because a method of detecting structural change in the cytoplasmic region has been limited. We have recently applied a method of genetical incorporation of fluorescent unnatural amino acid, Anap, to the cytoplasmic region of Ci-VSP (sea squirt Ciona intestinalis VSP) which was expressed in Xenopus oocyte. This method enables detection of fine structural change reported by fluorescence intensitiy without perturbing the local protein structure. Voltage-dependent fluorescence change of Anap showed two bidirectional changes along the voltage, decrease at low membrane depolarization and increase at higher depolarization, suggesting that the structure of the cytoplasmic region takes multiple conformations. By applying the method to different constructs of Ci-VSP with altered enzyme activity, we obtained evidence that the enzyme takes at least two activated states with distinct magnitude of enzyme activity. Given that voltage sensor of Ci-VSP takes multiple states during activation, it will be intriguing to see in the future how individual enzyme states correlate with states of the voltage sensor.

Annonce de séminaire


Lundi 24 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Edgar Gomes

Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

Mechanisms of nuclear positioning during myofiber formation

Invité par Bénédicte Chazaud

Résumé

Connecting the nucleus to the cytoskeleton is relevant for multiple cellular processes and disruption of these connections result in multiple pathologies. Nuclear positioning within cell cytoplasm requires de connection between nucleus and the cytoskeleton. We are interesting to understand the processes involved in these connections and the role for nuclear positioning in cell function. We study cell migration and skeletal myofiber formation which required the connection between the nucleus and the cytoskeleton and precise nuclear positioning. We use different molecular and cellular approaches in combination with time-lapse imaging analysis to address these questions.

Annonce de séminaire


Jeudi 27 Septembre à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est

Rashmi KOTHARY

Centre for Neuromuscular Disease University of Ottawa

Spinal Muscular Atrophy: a multi-organ disease

Invité par Patrick Lomonte

Abstract

Spinal Muscular Atrophy was characterized in the late 1800s but it was almost 100 years later that the genetic cause was identified as a mutation in the human SMN1 gene. While humans do have two genes that code for SMN, SMN2 only produces 10% protein when compared to SMN1. Early work with mouse models was complicated by the fact that mice only have the one Smn gene which when mutated results in preimplantation lethality. This problem was solved by the development of a mouse model incorporating human SMN2 gene, which was for years the only viable mouse model. Now, there are over a hundred mouse models available that have served to inform our understanding of pathogenesis in SMA.
Classically, SMA is described as a motor neuron disease; however, SMN is expressed ubiquitously throughout the body. In fact, SMA is emerging to be a multi-organ disease with SMN depletion having impacts on many tissues in the body. Subcutaneous administration of available treatments may address these affected organs better than intrathecal administration. Also, systemic gene therapies that are currently under development may help repair function in these other organs.
Dr. Kothary will present on the work in his laboratory on the multi-organ nature of SMA. Defects in various tissues will be discussed.

Annonce de séminaire


Juin 2018

Vendredi 29 Juin à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est – 3ème étage

Laure STROCHLIC

Institut de Myologie – Centre de Recherche en Myologie, Sorbonne Université, INSERM AIM UMRS974, Paris

Regulation of neuromuscular connectivity by Wnt signaling from signaling molecules to therapeutic strategies

Invité par Rémi Mounier

Résumé

The development and maintenance of the neuromuscular connectivity relies on a temporally fine-tuned balance of distinct bi-directional communication between motor neurons and their muscle targets. Disruption of this communication leads to structural and functional defects that affect the motor function and causes severe neuromuscular pathologies. Wnt signaling participates in various developmental mechanisms such as migration, axonal guidance or synaptogenesis. But how the Wnt signaling network could regulate neuromuscular connectivity and how it could affect motor function is unknown. In this presentation, I will provide data using Wnts gain or loss of function studies in cell culture or in mice showing that distinct branches of Wnt signaling, acting in part via the muscle-specific kinase MuSK regulate several key aspects of the formation and maintenance of the neuromuscular synapse including pre and postsynaptic differentiation/stabilization, retrograde control of motor axon outgrowth and synapse-specific gene expression. I will also present evidence showing that the pharmacological modulation of Wnt signaling in a pathological context could be used as a therapeutic strategy to counteract neuromuscular junction (NMJ)- associated disorders. Overall, our results provide novel insights into the mechanisms by which synaptic diffusible cues act to prevent NMJ dysfunction, muscle weakness and disease.

Dans cette présentation, je fournirai des données, utilisant des approches expérimentales in vitro et in vivo chez la souris, qui montrent le rôle émergent de la signalisation Wnt dans la régulation de la connectivité neuromusculaire dans un contexte physiologique et pathologique.

Annonce de séminaire


Mai 2018

Vendredi 4 Mai à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Helge AMTHOR

Université de Versailles – Paris Saclay Laboratoire U1179 UVSQ – INSERM

BMP signaling controls limb muscle development and maintenance

Invité par Laurent Schaeffer

Résumé
Bone morphogenetic proteins (BMPs) regulate the activity of skeletal muscle precursors as well as the trophic state of differentiated muscle. Here, the role of BMP signaling was explored at different stages of limb muscle development by overexpressing an inhibitory Smad protein (Smad6) to abrogate the BMP signaling cascade at cell autonomous level. Overexpression of Smad6 in limb muscle precursors during development (crossing Rosa26-Lox-Stop-Lox-Smad6-IRES-GFP mice, termed RS6, with Lbx1Cre/+ transgenic mice) disturbed limb muscle myogenesis: early myogenic markers Pax3 and MyoD were strongly downregulated, fetal limb muscles were smaller, consisted of fewer myofibers and displayed a disturbed muscle patterning. Overexpression of Smad6 in postnatal muscle precursors (using RS6: Pax7CreERT2/+ mice) caused decreased cell proliferation resulting in smaller myofibers containing less myonuclei and in decreased generation of satellite cells. Overexpression of Smad6 in differentiated muscle resulted in a different phenotype (using RS6:HSA-Cre mice): limb muscles were only modestly smaller, however, consisted of fewer but larger myofibers with increased myonuclear number. Overexpression of the BMP antagonist Noggin in adult muscle (loss-of-function) resulted in muscle fiber atrophy, whereas overexpression of the BMP receptor Alk3 (gain-of-function) caused muscle fiber hypertrophy. These latter effects were likely muscle precursor independent, as overexpression of Smad6 in differentiated fibers (using RS6:Pax7CreERT2/+ mice) had no effect on satellite cell number and muscle size in the adult. In conclusion, the role of BMP signaling in skeletal muscle is stage and context specific.

Annonce de séminaire


Mercredi 16 Mai à 11:00 – Salle des Pas Perdus, 1er étage

Vanina ROMANELLO

Venetian Institute of Molecular Medicine, Padova

The role of the myokine FGF21 in skeletal muscle homeostasis

Invité par Rémi Mounier

Résumé
Skeletal muscle is a major site of metabolic activity and the most abundant tissue in the human body accounting for almost 40% of the total body mass. It is a plastic tissue that adapts to changes in exercise, nutrition and hormones, which also induces the release of myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine and endocrine effects, explaining how muscles regulate metabolic homeostasis in other tissues. These systemic effects help to explain why physical activity, and thereby muscle recruitment, elicits several beneficial effects in many different diseases. Indeed, exercise preserves and ameliorates mitochondrial function and muscle metabolism, thereby affecting the release of myokines and metabolites that systemically counteract organ deterioration. We have recently proposed an interplay between the myokine Fgf21 and the mitochondrial quality control pathways that greatly contributes to a pro-senescence metabolic shift. However, even though the myokine field is exponentially increasing, little is known about their role in muscle homeostasis.

Annonce de séminaire


Jeudi 31 Mai à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Robert J. Johnston

Johns Hopkins University, Baltimore, USA

Stochastic gene expression and nuclear architecture in fly eyes and human retinal organoids

Invité par Thomas Boulin

Résumé
A central challenge in developmental neurobiology is to understand how the myriad types of neurons in the human nervous system are generated. Stochastic gene expression mechanisms are crucial to differentiate neuronal subtypes and expand function. During stochastic fate specification, individual neurons randomly choose between different fates, resulting in unique patterns but consistent proportions of cell types among genetically identical organisms. My lab studies the stochastic mechanisms that specify the color-detecting photoreceptors in the fly and human retina. Fruit flies have a well-characterized retina and an abundance of genetic tools that enable molecular analyses of gene regulatory mechanisms. To overcome the challenges associated with human studies, we have developed a human retinal organoid system that recapitulates retinal development and photoreceptor specification. With these systems, we are interrogating how DNA elements, trans factors, and chromatin architecture control random on/off gene expression. Our molecular approaches are complemented by quantitative genetics to determine how natural variation in the genome impacts gene expression and photoreceptor specification. Finally, we conduct behavioral and functional assays to measure differences in color perception when photoreceptor fates are altered. By studying highly divergent organisms from multiple angles, we aim to define the unifying principles underlying stochastic fate specification during nervous system development.

Annonce de séminaire


Avril 2018

Vendredi 6 Avril à 11:00 – Salle des Pas Perdus, 1er étage

Athanassia SOTIROPOULOS

Institut Cochin, Paris

Role of Srf transcription factor and F-actin scaffold in muscle stem cell fusion

Invité par Rémi Mounier

Résumé
Our team is interested on how signaling pathways control of adult skeletal muscle plasticity. In the past years, we focused our attention on Srf transcription factor which is one of the three master genes that controls myogenesis in Caenorhabditis elegans, together with MyoD and HAND. We investigated the role of Srf in two cellular compartments of mouse skeletal muscle (myofibers and adult muscle stem cells) upon different perturbation of muscle homeostasis (hypertrophy, atrophy, regeneration). In the present seminar, I will summarize our findings concerning the role of Srf in myofibers to control muscle mass and I will present recent data identifying Srf as a master regulator of muscle stem cell fusion and demonstrating the implication of F-actin architecture in this process.

Seminar announcement


Mars 2018

Vendredi 16 mars à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Cécile MARTINAT

INSERM/UEVE UMR861, I-STEM, AFM

Human pluripotent stem cells for the study and treatment of neuromuscular diseases : myth or reality ?

Résumé
Neuromuscular diseases correspond to a vast group of diseases that perturbs the function of the skeletal muscles by affecting motoneurons, muscles and/or NMJs. To date, no efficient curative treatments have been identified for NMD. Progresses towards identification of new treatment have been hampered by the incomprehension of disease pathogenesis, particularly in early phases, as well as the availability of relevant screening tools. Disease-specific human pluripotent stem cells, from embryonic origin or derived from reprogramming somatic cells, offer the unique opportunity to have access to a large spectrum of disease-specific cell models. Due to their ability of self-renewal and differentiation into various tissues affected in each pathological condition, the development of these human disease-specific pluripotent stem cells provide new insights in pathological mechanisms implicated in human diseases for which, accessing homogenous affected tissues is often challenging. Validating this concept, we previously demonstrated that human pluripotent stem cells and derivatives which, express the causal mutation implicated in the Myotonic Dystrophy type 1 (DM1), offer pertinent disease-cell models, applicable for a wide systemic analysis ranging from mechanistic studies to therapeutic screening. Thus, we identified, through a genome-wide analysis, two early developmental molecular involved both in myogenesis as well as in neurite formation and establishment of neuromuscular connections. These neuropathological mechanisms may bear clinical significance as related to the functional alteration of neuromuscular connections associated with DM1. In parallel to these functional pathological studies, we also demonstrated the pertinence of this new disease-specific cell model to identify new therapeutic strategies. Thus, our results identified the possibility to repurposing metformin, the most commonly prescribed drug for type 2 diabetes, for DM1 leading to a phase 2 clinical trial that is actually ongoing.
We are now extending our approach to another incurable neuromuscular disease, spinal muscular atrophy (SMA). This disease, considered as the leading genetic cause of infant death, is due to mutations or deletions in the « Survival of Motor Neuron » gene, SMN1, which results in low levels of the expressed SMN protein. Despite this ubiquitous SMN expression, the pathology is characterized by degeneration of spinal Motor neurons whereas other neuronal types are relatively preserved suggesting that spinal motor neurons specific features control this differential sensitivity. Based on our recent development allowing the efficient and robust conversion of human pluripotent stem cells into affected spinal motor neurons and non- affected cranial motor neurons, our objective is to deepen the mechanisms involved in the specific degeneration of spinal motor neurons in SMA as well as the mis communication of these neurons with their muscular target.

Annonce de séminaire


Lundi 19 Mars à 10:00 – Amphi 4 – 4e étage

Christoph Hoefer, M. Sc.

Senior Business Development Manager ; Life Sciences Solutions, Cell Biology, ThermoFisherScientific

Séminaire Technique : Travailler avec des iPSC (induced Pluripotente Stem Cell)

Résumé
Les cellules souches pluripotentes humaines (iPSC) sont des outils puissants pour la recherche en biologie du développement, la médecine régénérative et l’étude des pathologies humaines. Les données obtenues à partir de modèles physiologiques in vitro amélioreront grandement notre compréhension des processus biologiques. Dans cette présentation, j’aborderai les principaux défis rencontrés dans la mise en place des cellules souches pluripotentes au sein d’un laboratoire et les améliorations récentes apportées à la construction de modèles pour les maladies humaines, telles que la reprogrammation, l’expansion, la transfection, la préservation et la différenciation efficace de iPSC, ainsi que les options de modifications génomiques.

Annonce de séminaire


Vendredi 2 Mars à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Nicolas PLACE

Institute of sport Sciences, University of Lausanne

Skeletal muscle adaptations to exercise : a translational approach

Invité par Julien Gondin

Résumé
The amount of force skeletal muscles can produce depends on their contractile history. For instance, repeated contractions generally lead to reduced muscle force generating capacity, namely muscle fatigue. Although muscle fatigue has been the focus of many works in the last 100 years, the underlying mechanisms remain elusive. In this presentation, special emphasis will be given to the role of Ca2+ handling as a key regulator of (i) muscle weakness and (ii) beneficial adaptations observed after high intensity interval training. In particular, the potential role of the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor type 1, will be discussed.

Annonce de séminaire


Lundi 5 Mars à 14:00 – Salle des Conférences – Médiathèque Paul Zech

Julien OCHALA

Faculty of Life Sciences & Medicine, King’s College, London

Actinopathies : From Mutations to Treatment

Invité par Laurent SCHAEFFER

Résumé
Actinopathies are genetically and clinically heterogeneous disorders mainly characterized by generalized muscle weakness. The understanding of this group of disorders has advanced in recent years through the identification of the causative mutations in the gene encoding one of the major proteins of the basic contractile unit of skeletal muscle, i.e., actin. In the present seminar, I will present (i) how these gene mutations lead to generalized muscle weakness and (ii) the advances regarding potential therapies.

Annonce de séminaire


Février 2018

Vendredi 9 Février à 14:00 – Salle des Conférences – Médiathèque Paul Zech

Norbert WEISS

Institute of Organic Chemistry and Biochemistry, Prague

Trafficking of T-type calcium channels in health and disease

Invité par Vincent JACQUEMOND

Résumé
T-type calcium channels are key contributors to neuronal physiology where they shape electrical activity of nerve cells and contribute to the release of neurotransmitters. Alteration of T-type channel expression has been causally linked to a number of pathological conditions including neuropathic pain and absence seizure activity. Although a number of signaling pathways regulating the activity of T-type calcium channels have been reported, the molecular machinery and signaling molecules controlling the trafficking and expression of the channel protein at the plasma membrane remain largely unknown. I will present some of the basic mechanisms recently identified controlling the physiological trafficking of T-type channels, and illustrate how metabolic defects or congenital mutations can disturb this trafficking machinery and eventually leading to disease conditions.

Annonce de séminaire


Janvier 2018

Mardi 30 janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Isabelle JANOUEIX

Institut Curie – Inserm U8330, Paris

Understanding neuroblastoma biology through the analysis of its genetic and epigenetic landscapes

Invité par Valérie Castellani

Résumé
Neuroblastoma is an embryonal neoplasm arising from the peripheral nervous system that accounts for 15% of cancer deaths in childhood. It is an enigmatic tumor presenting with a great genetic and clinical heterogeneity, both in terms of presentation and outcome.
The characterization of the genetic alterations observed in neuroblastoma led to the identification of major players of neuroblastoma oncogenesis that has considerably improved our understanding of the biology of this pediatric cancer. More recently, the analysis of the super-enhancer landscape allowed to decipher the core regulatory circuitries controlling the gene expression program of neuroblastoma. Distinct transcription factor networks predicate different tumor identities, corresponding to sympathetic noradrenergic or mesenchymal/neural-crest cell like identities. Cells of mesenchymal identity are more resistant to chemotherapeutic agents. Moreover, some neuroblastoma cells exhibit plasticity and are able to shift between the NCC-like and noradrenergic identities.
The understanding of cell identity, heterogeneity and plasticity in neuroblastoma has strong implications with respect to the development of new therapeutic strategies to eradicate tumor cells in neuroblastoma patients.

Annonce de séminaire


Mercredi 10 janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Justin FALLON

Brown University, Providence, RI

MuSK as a BMP co-receptor

Invité par Laurent Schaeffer


Décembre 2017

Vendredi 1er Décembre à 11:00 – Amphithéâtre CNRS

Chantal Thibert

Institute for Advanced Biosciences, Université Grenoble Alpes

The tumor suppressor LKB1 controls cell fate through pyruvate-alanine transamination

Invité par Julien Courchet

Résumé
The tumor suppressor LKB1 (also named STK11) codes for a serine/threonine kinase. LKB1 acts as a key regulator of cell polarity as well as energy metabolism partly through the activation of the AMP-activated protein kinase (AMPK), a sensor that adapts energy supply to the nutrient demands of cells facing situations of metabolic stress.
To determine if Lkb1 exerts a coordinated regulation of energy metabolism and cell polarity, we deleted the Lkb1 gene in polarized cells and explored the metabolic consequences. In particular, we generated spatio-temporal ablation of Lkb1 in a subpopulation of mouse embryonic multipotent neural crest cells (NCC) that originate from the neural tube and give rise to a broad range of derivatives including most of the face, the melanocytes, the peripheral nerves and the enteric nervous system (ENS). Mutant mice exhibited craniofacial malformations, hypopigmentation, intestinal pseudo-obstruction and hindlimb paralysis. Further phenotypic characterization revealed that LKB1 is required for the differentiation and maintenance of two NCC-derivatives, Schwann cells and the ENS. Using a model of neural crest stem cell line, we demonstrated that Lkb1 is key for neural crest-derived glial commitment. Mechanistically, Lkb1 loss led to an increase of alanine and glutamate levels and inhibition of pyruvate-alanine transamination rescued glial differentiation of Lkb1-null NCC, in a mTOR dependent manner. Furthermore, AICAR, an analogue of AMP, rescued glial differentiation of Lkb1-deficient NCC and corrected the Schwann cells and ENS phenotypes of Lkb1 mutant mice.
Altogether, these findings highlight the central role of Lkb1 during neural crest cell lineage and uncovered a link between Lkb1-mediated pyruvate-alanine cycling and glial commitment. These results provide also new insights for the understanding of metabolic events that contribute to the formation of LKB1-deficient malignancies.

Annonce de séminaire


Novembre 2017

Vendredi 10 Novembre à 11:00 – Amphithéâtre CNRS

Michalis Averof

Institut de Génomique Fonctionnelle de Lyon (IGFL).

Live imaging of regenerating legs: cell dynamics and progenitors

Invité par Rémi Mounier

Résumé
Regeneration is a complex and dynamic process, mobilising diverse cell types and remodelling tissues over a long time period. Compared with embryonic development, it is less genetically tractable and less accessible for direct observation. I will describe our recent efforts to establish a small crustacean, Parhyale hawaiensis, as an experimental model for studying regeneration. Using transgenic markers and live imaging we are starting to describe the cell behaviours and progenitors that underpin limb regeneration. We find that crustacean limb regeneration relies lineage-committed progenitor cells: muscles derive from satellite-like stem cells, whereas epidermis regenerates from existing epidermal cells.

Annonce de séminaire


Octobre 2017

Jeudi 12 Octobre à 11:00 – Salle Fontanes, Darwin D

Damaris Lorenzo

University of North Carolina at Chapel Hill

Ankyrin-B and beta-II spectrin in axonal transport and brain connectivity

Invité par Thomas Boulin

Résumé
The formation, targeting, and maintenance of axon and dendrites are critical for proper brain development and synaptic function. Deficits in synapse establishment and maturation can lead to neurodevelopmental, neurodegenerative, and psychiatric disorders. The neuronal cytoskeleton regulates the architecture and dynamics of synaptic processes by providing structural support and the tracks for motor protein-based synaptic transport. The latter is particularly important for the establishment of long axonal projections, which requires coordinated long-range organelle transport. The membrane associated adaptor ankyrin-B (AnkB) promotes fast axonal transport and elongation by coupling dynactin to multiple organelles through binding to phosphatidylinositol 3-phosphate lipids in these cargos. Additionally, AnkB directly binds βII-spectrin, which, in turn, controls the formation of a ring-shaped membrane periodic skeleton (MPS) in axons and mature dendrites. Interestingly, βII-spectrin also associates with molecular motors. I will show that AnkB and βII-spectrin are key elements in independent and overlapping pathways responsible for the transport of synaptic cargo and other organelles, and are essential for establishing proper brain structural and functional connectivity.

Annonce de séminaire


Mai 2017

Vendredi 12 mai à 11:00 – Amphithéâtre CNRS

Andre Brown

MRC London Institute of Medical Sciences – Imperial College, London

Syntax in C. elegans locomotion

Invité par Thomas Boulin

Résumé
Behaviour is a striking phenotype and often one of the first things we notice about an animal. Broadly speaking, we are interested in understanding how genes affect behaviour, but despite rapid advances in technology for sequencing and engineering genomes, it is still a challenge to associate particular genes with heritable behavioural differences because behaviour is time consuming to measure and difficult to quantify. We are using automated imaging to record the behaviour of freely moving nematode worms and developing new analysis methods to extract relevant features. I will discuss unsupervised methods to quantify behavioural repertoires, and how making connections to language processing and data compression can give insight into the structure of behaviour. Finally I will show how these new representations can advance the study of behavioural genetics and phenotypic drug screening.

Annonce de séminaire


Mercredi 17 mai à 14:00 – Salle Guillermond – Bât. L’Herbier

Hélène CASTEL

Normandie Rouen University / Inserm 1239 – Équipe Astrocyte and Vascular Niche

Cancer and Cancer treatments on cognition: A major translational impact of the preclinical research

Invité par Virginie DESESTRET

Résumé
Co-head Cancer and Neurosciences axis Northwest canceropole, Cancer and cognition platform; ICCTF member (editing of preclinical research guidelines).
The emergence of a new field in oncology addressing cognitive deficits in cancer patients is justified by the existence of deficits in memory, concentration and attention, as well as executive functions before, during and after treatments, symptoms often referring to the “chemofog” or “cancerfog”. Our work mainly involves research and clinical groups of Normandie developing programs in patients and animal models, to improve our understanding of the impact of cancer and its treatments on cognitive functions. Two main examples of these translational studies we participated on can be exposed:
The first Cog-Age clinical study (Pr F. Joly, Baclesse Caen) showed that cognitive decline can be detected 6 months after chemotherapy in breast cancer elderly patients. In a mirror study, chemotherapy administration in young and elderly mice resulted in a change in behavioral flexibility and alteration of neuron precursor proliferation in the hippocampal dentate gyrus. We were thus able to conclude that age-related cognitive decline is accentuated by chemotherapy, providing basis for questioning the place of adjuvant chemotherapy in this elderly patient population. The second clinical study COG-ANGIO (Pr Joly) demonstrated that antiangiogenics exert a direct negative impact on cognitive functions and fatigue in kidney cancer patients. In mice, the anti-angiogenic mTOR inhibitor everolimus did not alter cognitive functions but led to weight loss and modification of cell metabolism in brain regions involved in sleep/wake cycle or food intake, likely connected to fatigue. On the other hand, immunoneutralizing VEGF (Genentech-Roche, MTA) impaired spatial learning performance and neuronal activity of CA3 hippocampus neurons. These data suggest that a careful and systematic evaluation of targeted cancer therapies on cognitive functions in preclinical models may constitute a strategy of prevention by selection of treatments exhibiting minimum brain co-morbidities.
Together, this translational program is developed within the National Cancer and Cognition Platform (CNO/Ligue Nationale contre le cancer), with the aim to collaborate in a structured way with French oncology groups, research teams as well as pharmaceutical industry, by providing preclinical models and guidance on standard operating procedures for ancillary or future studies in identified population at risk.

Annonce de séminaire


Mars 2017

Vendredi 31 Mars à 11:00 – Salle FONTANNES – Bât. Darwin D RdC

Kei Sakamoto

Institut des Nestlé Institute of Health Sciences SA, Lausanne.

Key signaling players in the control of hepatic gluconeogenesis — AMPK or other AMPK-related/AMP-regulated enzymes ?

Invité par Rémi Mounier

Résumé
Hepatic glucose production is a key physiologic process that ensures energy balance for glucose-dependent organs/cells such as brain. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type 2 diabetes. LKB1, originally identified as a tumor suppressor protein, is currently thought as a critical regulator of cellular metabolism and growth by controlling the activity of AMP-activated protein kinase (AMPK) and also 12 other kinases that are closely related to AMPK. Among those AMPK-related kinases, we have recently identified that Salt-Inducible Kinase (SIK) plays an important role as a gluconeogenic gatekeeper in the liver.
Metformin exerts its major effect via inhibition of hepatic glucose production. This is thought to be mediated through decreased hepatic energy charge (i.e. increasing AMP/ATP ratio) via inhibition of mitochondrial respiration. The long-standing belief that 5’-adenosine monophosphate (AMP)-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged in experiments using mice lacking hepatic AMPK. I will discuss our recent data demonstrating AMP-mediated allosteric inhibition of an enzyme involved in gluconeogenesis plays a key role in acute glucose-lowering effect of metformin.

Annonce de séminaire


Janvier 2017

Jeudi 12 Janvier à 14:00 – Amphithéâtre CNRS

Alexandre Pattyn

Institut des Neurosciences de Montpellier, INSERM U1051. France.

Heterogeneous precursor populations underlie developmental plasticity of the dorsal root ganglia

Invité par Valérie Castellani

Résumé
Although a variety of primary sensory neurons are implicated in the detection and transmission of different sensory modalities, how they arise during development remains poorly understood. The process of neuronal specification is the acquisition of definitive phenotypic characteristics for a given subclass of neurons during embryonic development. This acquisition can be divided into several interdependent and sequential phases, from the time point when progenitor cells exit the cell cycle toward the newly formed and perfectly differentiated neuron. Using mouse genetics, Alexandre demonstrated that transcriptions factors of Maf and Zeb families control the specification and differentiation of specific sensory neuron sub-types. His work contributed to uncover the complex developmental sequence ensuring the formation of the peripheral sensory system and to highlight the progenitor diversity that underlies the developmental plasticity of sensory neuron generation.

Annonce de séminaire


Jeudi 19 Janvier à 11:00 – Salle FONTANNES – Bât. Darwin D RdC

Georgia Rapti

The Rockefeller University, Shaham lab, New York, USA.

It takes two to tango with elegance: Glia and pioneer neurons orchestrate C. elegans brain assembly

Invité par Jean-Louis Bessereau

Résumé
Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet, the identities of the pioneer-neurons and of their guidance-substrates and their interactions, are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans possesses radial-glia-like cells key for assembly initiation. Glia guide pioneer and follower axons using distinct signals. Pioneer neurons we identify, with unique growth properties, anatomy, and innervation, cooperate with glia to guide follower axons. We identified a CHIN-1/Chimaerin- KPC-1/Furin double mutant that severely disrupts assembly, unlike previously known mutants. CHIN-1/Chimaerin and KPC-1/Furin cooperate non-canonically in glia and pioneer neurons for guidance-cue trafficking. We exploit this genetic bottleneck to define a guidance-gene network governing assembly, with specific glia and pioneer-neuron contributions. Our studies reveal previously-unknown roles for glia in pioneer-axon guidance, and suggest conserved principles of brain formation.

Annonce de séminaire


Décember 2016

Jeudi 8 Décembre à 14:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Sophie Creuzet

Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Gif-sur-Yvette. France.

Neural crest in forebrain development: from embryology to pathophysiology

Invité par Valérie Castellani

Abstract
In my group, we study the neural crest, a unique cell population that emerges from the primitive neural field and which has a multi-systemic and structural contribution to vertebrate development. Over the last decade, I have been dedicating myself to the cellular and molecular background of the observation I made in 2004, that the cephalic neural crest (CNC), exerts an autonomous and prominent control on forebrain development. This notion has broken the traditional view of how the brain develops. By using exquisite grafting experiments in combination with focal spatially and temporally controlled transgenesis, we have discovered the unexpected and potent “paracrine role that the CNC exerts on forebrain growth and patterning early in development and documented this mechanism at the level of cell interaction, signalling and gene expression. We are now following this exiting line of research, which revisits fundamental concepts in Neurosciences. This notion provides also a conceptual renewal, which is biomedically relevant. The mechanisms identified so far in our model are conserved across tetrapodes, but some social behavioural features are specific to amniotes. Our ongoing project and future directions are to explore the aetiology of neural disorders and behavioural impairments in Humans and in the light of CNC dysfunctions.

Annonce de séminaire


Novembre 2016

Lundi 14 Novembre à 11:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Colin Crist

Department of Human Genetics, McGill University – Québec, Canada.

Translational Control of Muscle Stem Cells

Invité par Rémi Mounier

Abstract
Regeneration of adult tissues depends on somatic stem cells that remain quiescent, yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that accumulating transcripts specifying the myogenic program are not translated in quiescent satellite cells, but are repressed by the action of microRNAs and RNA binding proteins. Furthermore, the reversible nature of microRNA dependent silencing mechanisms may underlie the rapid activation of satellite cells that are poised to enter the myogenic program. We also show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2 at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2 exit quiescence, activate the myogenic program and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Finally, we show that addition of small molecule inhibitors of eIF2α dephosphorylation to muscle stem cell cultures permits their ex vivo expansion and engraftment into a preclinical mouse model of Duchenne muscular dystrophy.

Annonce de séminaire


Jeudi 17 novembre – 11:00 – Amphithéâtre CNRS

Michael A Rudnicki

Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Molecular regulation of muscle stem cell asymmetric division

Invité par Bénédicte Chazaud

Abstract
We discovered that a subset of satellite cells in skeletal muscle are self-renewing stem cells that give rise to myogenic progenitors through asymmetric apical-basal cell divisions. The regulation of asymmetric stem cell division is a key control point that impacts the efficacy of the entire regenerative program. Stem cell polarity is established by the PAR complex, comprised of PAR3/PAR6/aPKC, to regulate self-renewal and expansion. Duchenne Muscular Dystrophy (DMD) is coaused by a lack of dystrophin which is expressed in muscle fibers where it plays a role in ensuring structural integrity. We have made the seminal finding that dystrophin regulates the establishment of PAR-mediated polarity in satellite cells. In the absence of dystrophin, the polarity effector Par1b is dysregulated, leading to the failure of Par3 to become localized to the cortex associated with the basal lamina. Importantly, this results in an abnormal increase in centrosome number, a 10-fold reduction in the numbers of satellite stem cells undergoing asymmetric divisions, and a marked decrease in the generation of myogenin-expressing progenitors. Accordingly, our data suggests that the failure of regenerative myogenesis to keep pace with disease progression in DMD is not due to muscle stem cell exhaustion, but rather is due to a cell-autonomous deficiency in asymmetric division.

Annonce de séminaire


Mardi 22 novembre – 14:00 – Amphithéâtre CNRS

F. Jeffrey Dilworth

Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Epigenetic control of stem cell fate decisions in muscle repair

Invité par Bénédicte Chazaud

Abstract
During muscle regeneration, the conversion of muscle stem cells to terminally differentiated myofibers requires multiple cell fate transitions. Each of these transitions necessitates an alteration in the set of genes being expressed within the cell. In this presentation, our studies on the role of transcription factors and epigenetic enzymes in dictating changes in muscle gene expression will be highlighted. In particular, I will focus on the role for the antagonism between various transcription factors and epigenetic enzymes in controlling the commitment of muscle stem cells towards alternate cell fates.

Annonce de séminaire


Past Seminars

Octobre 2016

Vendredi 21 Octobre à 11:00 – Amphithéâtre CNRS

Fabien Le Grand

Center of Research in Myology, Université Pierre et Marie Curie Paris – France.

Control of muscle stem cell fate by Wnt signaling pathway(s)

Invité par Bénédicte Chazaud

Abstract
Regeneration of the adult skeletal muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). Upon activation following injury or repeated exercise, MuSCs leave quiescence to proliferate and then differentiate to form new muscle fibers while a sub-population exit the cell cycle to self-renew and replenish the stem cell niche. In the course of this process, signals from the microenvironment instruct cycling MuSCs and control myogenesis. We previously demonstrated that numerous Wnt molecules are secreted in the local milieu during regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP signals sent by the regenerating myofibers. To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific ß-catenin Loss-Of-Function or Gain-Of-Function. Strikingly, we observed that induction of either ß-catenin LOF or GOF mutations in MuSCs leads to the impairment of skeletal muscle regeneration following injury. By using a mouse model of conditional APC gene deletion in MuSCs we further demonstrated that the massive activation of canonical Wnt signaling in MuSC following APC loss results in defective cell cycle progression and apoptosis. Mechanistically, we observed that Wnt/ß-catenin signaling orchestrates the cytoplasmic relocalization of the histone 3 lysine 9 methyltransferase Setdb1 during differentiation. We further showed that Setdb1 is required for MuSCs amplification and suppresses myoblast terminal differentiation. Genome-wide analyses showed a Wnt3a-dependant release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation. Taken together, our results demonstrate that both canonical and non-canonical Wnt pathways are necessary for MuSC function. Lastly, I will discuss the potential cross-talks between these two faces of an important signaling.

Annonce de séminaire


Mercredi 5 Octobre à 11:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Stefan Dimitrov

Institut Albert Bonniot, Centre de Recherche UGA – INSERM U1209 / CNRS UMR 5309, Grenoble, France.

Epigenetic strategies : nucleosome remodeling, histone modifications and histone variants.

Invité par Laurent Schaeffer

Abstract
Chromatin impedes the binding of protein factors to the underlying DNA sequences. The cell uses three main “epigenetic tools” to overcome the chromatin barrier, namely, chromatin remodelers, histone variants and histone post-translational modifications. We will give specific examples of how either one of these “epigenetic tools” functions.
Chromatin remodelers are sophisticated nano-machines, which are able to alter histone-DNA interactions and to mobilize nucleosomes. Neither the mechanism of their action nor the conformation of the remodeled nucleosomes are, however, yet well understood. We have studied the mechanism of RSC-induced chromatin remodeling by using high resolution microscopy and state of the art biochemistry techniques. The data illustrates how RSC remodels the nucleosome in vitro and shed light on its in vivo function. The crystal structure of the CENP-A nucleosome was recently solved. Intriguingly, in contrast to the canonical nucleosome (where 147 bp of DNA are wrapped around the histone octamer), only the central 121 bp were visible, suggesting flexible CENP-A nucleosomal ends. Why the CENP-A nucleosome exhibits flexible DNA ends is totally unknown. Our data show that the flexible DNA ends of the CENP-A nucleosome are required for mitotic fidelity.
The Aurora family of oncogenic kinase consists of two major members, Aurora A and Aurora B. Both kinases exhibit very high homology. They show, however, quite distinct localization and function. Histone H3 is specifically phosphorylated, presumably by the oncogenic kinase Aurora B, at serine 10 at the onset of mitosis. Here we will present data on the distinct function of the two Aurora kinases and the mechanism of phosphorylation of histone H3 by Aurora B.

Annonce de séminaire

Vendredi 7 Octobre à 14:00 – Amphithéâtre CNRS

Stéphane Vassilopoulos

Institut de Myologie, UMRS 974 UPMC-Inserm / FRE 3617 CNRS, G. H. Pitié-Salpétrière, Paris – France.

The endocytic machinery in healthy and diseased muscle

Invité par Laurent Schaeffer

Abstract
Costameres represent specialized focal adhesion sites of muscle fibres, located between the plasma membrane and sarcomeres, the contractile units of muscle. When disrupted, they directly contribute to the development of several distinct myopathies.
We have shown that the ubiquitous clathrin heavy chain (CHC), well characterized for its role in intracellular membrane traffic and endocytosis from the plasma membrane (PM), forms large plaques connected to α-actinin and actin filaments. Depletion of CHC leads to defective costamere formation and maintenance both in vitro and in vivo and induces sarcomere disorganization and a loss of contractile force due to the detachment of sarcomeres from the PM. At costameres, CHC is co-expressed with dynamin 2 (DNM2), another key protein of the intracellular membrane trafficking machinery which is mutated in autosomal dominant centronuclear myopathy (CNM). We analyzed the role of DNM2 and several actin binding proteins on clathrin plaque function at costameres in vitro by using either siRNA depletion combined to high resolution electron microscopy or in vivo by intravital microscopy. We also focused on the possible link between costamere and CNM pathophysiology. Using myoblasts from DNM2-mutated patients and using myoblasts and muscles from a knock-in mouse model of DNM2-related myopathy, we analyzed structure of costameres by biochemical and immunocytochemical approaches, as well as their ultrastructure.
Our results demonstrate a crucial role for the endocytic machinery and the cytoskeleton. Their contribution to the formation and maintenance of the contractile apparatus highlight an unconventional role for clathrin flat lattices in skeletal muscle which may be relevant to pathophysiology of several neuromuscular disorders.

Annonce de séminaire

Septembre 2016

Vendredi 30 Septembre à 11:00 – Amphithéâtre CNRS

Sandrine Humbert

GIN – Inserm U1216 – University Grenoble Alpes, Grenoble, France.

Huntingtin regulates cortical development: consequences for Huntington’s disease

Invité par Julien Courchet

Abstract
The bulk of interest in the huntingtin protein has centered on the fact that, when mutated, huntingtin causes Huntington’s disease (HD), a devastating neurodegenerative disorder. The mutation causing HD is an abnormal polyglutamine stretch in huntingtin. Given the adult onset and dysfunction and death of adult neurons characterizing HD, most studies have focused on the toxic effects elicited by mutant huntingtin in post-mitotic neurons. However, the protein is ubiquitous and expressed in the developing embryo where it plays an essential role as revealed by the early embryonic lethality at day 7.5 of the complete knockout of the huntingtin gene in mouse. Anyway, the roles of the wild-type protein during development have been overlooked. I will discuss how huntingtin regulates several steps of mouse embryonic corticogenesis. I will also show the consequences of the presence of an abnormal polyglutamine expansion in huntingtin during cortical neurogenesis and consider the viewing of HD as a developmental disorder.

Annonce de séminaire


July 2016

Mardi 12 juillet a 11:00 – Amphithéâtre CNRS

Jan Tuckermann

Institute of Comparative Molecular Endocrinology Ulm University, Ulm, Germany.

Modes of GR action revised – Novel mechanisms of corticosteroids in inflammation and bone integrity

Invited by Bénédicte Chazaud

Abstract
The Tuckerman Laboratory made major contributions to the molecular mechanisms of corticosteroids in beneficial and side effects of steroid therapy. With the help of conditional and function-selective knockout mice for the glucocorticoid receptor (GR) the lab identified critical cell types and novel mechanisms for anti-inflammatory activities of glucocorticoids in different inflammatory disease models. Furthermore we made the discovery that in a model of lung inflammation the anti-inflammatory action of glucocorticoids is not dependent on the inhibition of pro-inflammatory mediators, but rather requires cooperation with pro-inflammatory signaling pathways (e.g. p38) to induce anti-inflammatory acting genes and alternative polarization of macrophages.

Annonce de séminaire


Juin 2016

Vendredi 24 juin à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Pierre-Jean Corringer

Pasteur Institute, Channel-receptor Unit, CNRS UMR 3571, 25 rue du Docteur Roux, 75015 Paris, France.

Pentameric ligand-gated ion channels functioning at the atomic resolution

Invited by Maëlle Jospin

Abstract
Pentameric channel-receptors, including nicotinic acetylcholine, glycine and GABAA receptors, play a key role in fast excitatory and inhibitory transmission in the nervous system and are the target of numerous therapeutic and addictive drugs. They carry several neurotransmitter binding sites which govern the opening of a transmembrane ion channel. Extensively expressed in animals, they were found in several bacteria, especially the homolog from the cyanobacteria Gloeobacter violaceus (GLIC) which functions as a proton-gated ion channel. The simplified architecture of this archaic homologue, as well as its prokaryotic origin, allowed solving its X-ray structure in several conformations. Those static structures suggest that channel opening occurs through symmetrical quaternary twist and “blooming” motions, together with tertiary deformation. We further engineered multiple fluorescent reporters on the structure, allowing investigating the dynamics of the allosteric reorganizations and showing that activation involves a key pre-active conformation. Finally, the GLIC system was exploited to solve the structure of human receptors through the generation of functional chimeras. Overall, our work gives insights into the mechanism of gating and pharmacological regulation of this important family of neurotransmitter receptors.


Mai 2016

 

Lundi 30 mai à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Yishi Jin

UC San Diego.

Mechanisms regulating synapse maintenance and neural activity

Invited by Jean-Louis Bessereau

Abstract
Synapses are organized subcellular structures that transmit information within the nervous system and to other parts of our body. Our studies use C. elegans have uncovered multiple pathways controlling synapse formation, maintenance and function. Using a genetic model mimicking the physiological state of seizures, our recent work have identified novel regulatory themes affecting presynaptic release machinery. We also discovered that a novel immunoglobulin superfamily (IgSF) transmembrane protein mediates synapse and non-neuronal tissue interaction in synapse maintenance. These findings have implications to our understanding of circuit malfunction under disease conditions.

Annonce de séminaire


Jeudi 26 mai à 11:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Francesco Zorzato

Department of Biomedicine, Basel University

Pathophysiology of ryanodinopathies

Invited by Bruno Allard

Abstract
Type 1 ryanodine receptor (RyR1) is preferentially expressed in skeletal muscle, and mutations in the gene have been associated with malignant hyperthermia, a pharmacogenetic disease, and with several congenital myopathies, including central core disease, multiminicore disease, centronuclear myopathy, congenital fibre type disproportion. Experimental data have indicated that RyR1 is also expressed in some areas of the central nervous system, in some cell types of the immune system and in smooth muscle cells. These results imply that mutations in the gene encoding RyR1 will not only affect skeletal muscles, but other tissues that express this calcium channel as well, thereby broadening the clinical spectrum of disorders due to RyR1 dysfunctions.
The RyR1 is of fundamental importance for the development of muscle force and a decrease in its content may be causally linked to the profound muscle weakness seen in patients with some forms of congenital myopathies linked to recessive RYR1 mutations. The protein composition of the junctional sarcoplasmic reticulum membrane encompassing the excitation-contraction coupling molecular complex (ECCMC) is extremely complicated. Polymorphic variants of the junctional sarcoplasmic reticulum protein JP45 have been shown to segregate in Malignant Hyperthermia Susceptible subjects of Malignant Hyperthermia families in the UK. Thus, some ECCMC accessory proteins may play a role not only in regulating excitation-contraction coupling but also as modifiers of the ryanodinopathies phenotype.

Annonce de séminaire

 


 

Jeudi 19 mai à 11:00 – Amphithéâtre de la délégation du CNRS

Dr. Jean-Marc Goaillard

UNIS – Aix Marseille Université

Biophysical networks underlying electrical phenotype of dopaminergic neurons

Invited by Thomas Boulin

Abstract
Any type of neurons can be easily identified based on its electrophysiological activity, such as its pattern of spontaneous activity, the shape of its action potential, its dendritic integration, etc. How is stability of such electrical phenotype achieved, what are its molecular principles, and what is the degree of robustness of electrical phenotype in the face of different perturbations are questions only very partially answered. We studied these questions on dopaminergic neurons of the substantia nigra pars compacta. Our work involved characterizing the electrical phenotype of these neurons and measuring its post-natal development and its stability at mature stages. We also characterized the specific relationships of electrophysiological parameters underlying the electrical phenotype. In order to determine how complex electrical phenotype is achieved, we then investigated the networks of co-regulation of ion channels at the genetic and at the protein levels. Our results suggest that ion channel gene expression and protein interactions display a modular structure that may be involved in stabilizing phenotype. We also show that electrical phenotype also presents such a modular structure. Our ultimate goal is to provide a systems-level approach to robustness of electrical phenotype.

Annonce de séminaire

 


 

Vendredi 13 mai à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Michele Zoli

 


Avril 2016

Friday Avril 29th at 14:00 – Amphithéâtre de la délégation du CNRS

Dr. Shiva Tyagarajan

Inst. of Pharmacology and Toxicology, University of Zurich.

Interrupting neuronal communication from a GABAergic viewpoint

Invited by Jean-Louis Bessereau

Abstract
In the brain distinct population of inhibitory GABAergic interneurons innervate principal glutamatergic neurons to regulate various aspects of brain function. At the postsynaptic compartment, specific GABAAR subunits are segregated to different neuronal compartments to recieve specific inputs from different interneurons. The correct interpretation of the incoming signal requires functional coupling between the presynaptic neurotransmitter GABA, postsynaptic GABAARs, and downstream signaling by postsynaptic density proteins. The main postsynaptic density protein at inhibitory synapse is gephyrin. In the past decade we have identified diverse signaling cascades that converge on gephyrin scaffold to regulate its scaffolding property, and in turn GABAergic neurotransmission. These studies have shed light into mechanisms that underlie dynamic changes in inhibitory neurotransmission, and how excitation shapes inhibition.

Annonce de séminaire

Janvier 2016

Vendredi 29 janvier à 14:00 – Bâtiment l’Herbier

Pura Muñoz-Cànoves

ICREA Research Professor at Universitat Pompeu Fabra, Barcelona.

Tissue regenerative decline with aging: focus on muscle stem cells

Invited by Bénédicte Chazaud

Abstract
Our group aims to understand the mechanisms regulating stem cell homeostasis and regenerative functions. Research is specially centered on stem cells of skeletal muscle (i.e., satellite cells). Recently, we have focused on two areas: 1) the functional decline of satellite cells with aging; and 2) the physiopathology of muscular dystrophies, with a specific interest in the contribution of inflammation and fibrosis to dystrophy progression. Concerning the first area, work from different laboratories has demonstrated that both environmental and cell- autonomous signals alter satellite cell regenerative potential with aging. I will discuss our latest results showing that satellite cells in their homeostatic quiescent state are equipped with quality control mechanisms to preserve their fitness, and how age-associate alterations in these protective mechanisms lead to stem cell loss of function and regenerative capacity.

Annonce de séminaire

Mai 2019

Lundi 13 Mai- 11:00 – Amphi 4

Marc HAMMARLUND

Yale University, New Haven, USA

How C. elegans neurons sense and respond to injury

Invité par Jean-Louis Bessereau

Abstract
The nervous system has an extraordinary capacity to repair damage by regenerating axons and synaptic connections. I will discuss the molecular and cellular basis of axon regeneration in C. elegans, and describe how regenerated synapses and circuits differ from those generated during development. Finally, I will present new data on a novel ncRNA pathway that controls regeneration.


Mercredi 22 Mai – 11:00 – Amphi 3

Luc BERTRAND

Université catholique de Louvain, Brussels

AMPK in cardiac pathologies, not just a metabolic sensor !

Abstract
The AMP-activated protein kinase (AMPK) has been firstly discovered to be activated under metabolic stress conditions such as myocardial ischemia. Its protective action during an ischemic episode has been demonstrated by several research groups. By targeting metabolism, AMPK helps the heart to survive under such deleterious conditions. However, AMPK action extends beyond metabolism and acute stress conditions. Indeed, it has been more recently shown that AMPK acts as protector of the heart in several chronic diseases such heart failure, diabetic cardiomyopathy and cardiac hypertrophy by acting in cardiomyocytes but also on the other cell types such as fibroblasts. Very recently, our group discovered a connection between AMPK and a particular post-translational modification called O-GlcNAcylation, this interplay acting a major role in the development of cardiac hypertrophy. The lecture will focus on the different protective roles of cardiac AMPK.


Vendredi 24 Mai – 11:00 – Salle Hermann

Michisuke Yuzaki

Keio University School of Medicine, Tokyo

Bridge over troubled synapses — a new synthetic synapse organizer

Invité par Jean-Louis Bessereau

Abstract
Synaptic organizers regulate formation, elimination and maintenance of synaptic connections throughout life. Although excitatory and inhibitory synaptic imbalance underlies certain neuropsychiatric and neurological disorders, no tools are currently available to directly modulate the balance. Recently, a new class of synaptic organizers, termed extracellular scaffolding proteins (ESPs), are reported to acutely and potently modulate specific synapses by directly binding to certain pre- and postsynaptic membrane proteins. Here, to expand the repertoire of ESPs with a variety of pre- and postsynaptic specificities, we developed a new synthetic ESP, Cbln1–neuronal pentraxin 1 (NP1) chimera (CPTX), by exploiting the structure of NP1 and Cbln1. Unlike original Cbln1, CPTX induced excitatory synapses by recruiting AMPA glutamate receptors in vitro. Furthermore, CPTX restored excitatory synapses and synaptic plasticity in vivo, as well as spatial and contextual memories in Alzheimer’s disease model mice. In this talk, I would like to discuss a possible toolkit of ESPs with a variety of pre- and postsynaptic specificities to modify neuronal circuits.


Mars 2019

Lundi 25 Mars à 14:00 – Salle Hermann

Saadi Khochbin

Institute for Advanced Biosciences, La Tronche, France

Les séminaires du Chromatin Club – Metabolism-driven epigenetics

Invité par Armelle Corpet / Patrick Lomonte

Annonce de séminaire


Février 2019

Vendredi 1 Février à 11:00 – Amphi 2bis

Frédéric RELAIX

INSERM – IMRB U955-E10, F-94010 Créteil, France

PAX3 controls the adaptive response of skeletal muscle stem cells to environmental stress

Invité par Rémi Mounier

Abstract
We have identified a molecular link between the Aryl hydrocarbon Receptor (AhR) environmental stress pathway and Pax3/Pax7 developmental genes during craniofacial development. Since Pax3/7 are key regulators of muscle stem cells (muscle satellite cells), we investigated the cellular and molecular impact of chronic 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) exposure on skeletal muscle and satellite cells in the adult. We combined in vivo and ex vivo approaches, in order to analyse the impact of chronic exposure to TCDD in several muscles such as tibialis anterior and biceps brachii. While all MuSCs express the transcription factor PAX7, we show that a muscle-specific subset also express PAX3 and exhibit resistance to environmental stress. Upon systemic TCDD treatment, PAX3-negative MuSCs display impaired survival, atypical activation and sporadic differentiation through the xenobiotic Aryl Hydrocarbon Receptor. We further show PAX3-positive MuSCs become sensitized to environmental stress when PAX3 function is impaired and that PAX3-mediated induction of mTORC1-dependent G(alert) is required for protection. Our study therefore identifies a functional heterogeneity of MuSCs in response to environmental stress controlled by PAX3.

Annonce de séminaire


Janvier 2019

Vendredi 25 Janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Nicolas RENIER

ICM – Institut du Cerveau et de la Moelle Epinière Paris – FRANCE

A framework for the study of behaviour and plasticity in the adult brain using light sheet microscopy

Invité par Julien Courchet

Abstract
There has been over the past 6 years a convergence in the fields of optics, biochemistry and computing leading to dramatic improvements in light sheet microscopy, tissue clearing protocols and image analysis algorithms. The convergence of these different fields has the potential to streamline brain studies by accelerating data acquisition speed and reliability over the current whole brain analysis pipelines based on serial sectioning methods. We previously developed the iDISCO+ protocol for immunostaining and imaging intact adult mouse brains. As a companion tool, we also developed and distribute ClearMap, an open source environment to segment objects and map them onto reference atlases optimized for large 3D datasets. We used this pipeline as a discovery tool to find brain regions active in correlation with various behaviors by mapping neuronal activity landscapes derived from Fos expression. Here, I will present recent unpublished projects made possible by our upcoming brain mapping pipeline ClearMap 2, expanding the repertoire of applications derived from intact whole brain preparations. We hope that ongoing developments in light sheet microscopy and image analysis pipelines will facilitate our understanding of individual variations in brain activity, connectivity and structure.

Annonce de séminaire


Novembre 2018

Vendredi 30 November à 11:00 – Salle des Pas Perdus – 1er étage – Faculté de Médecine Lyon Est

Hugues NURY

Institut de Biologie Structurale, Grenoble

Structures and transitions of the serotonin 5-HT3 receptor

Invité par Thomas Boulin

Abstract
The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel. It belongs to a large family of receptors that transduce signals across the plasma membrane​: upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions, which result in transient opening of a pore permeable ​to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression. I will present structures of the 5-HT3 receptor obtained by crystallography or cryo-electron microscopy. The structures, obtained in complex with inhibitors or agonists, represent snapshots in different states: inhibited, pre-active, active. Together with molecular dynamics simulations and functional recordings, they reveal the molecular mechanism of the fast neurotransmission mediated by 5HT3 receptors.

Annonce de séminaire


Vendredi 30 Novembre à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est

Emmanuel COMPE

Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch, Strasbourg

TFIIH and TFIIE mutations: when transcriptional deficiencies lead to neurological disorders

Invité par Ambra Giglia-Mari

Abstract
Trichothiodystrophy (TTD) is an autosomal recessive disorder mainly related to mutations in the DNA repair/transcription factor TFIIH. In addition to the typical dry and brittle hair, individuals with TTD develop neurological defects, including microcephaly and hypomyelination. Using a TTD transgenic mouse model, we previously observed a spatial and selective deregulation of thyroid hormone target genes in the brain, suggesting that transcriptional failures contribute to TTD phenotypes.
Remarkably, mutations within TFIIE, another general transcription factor, have been recently associated with TTD. Such observation prompted us to accurately dissect the partnerships occurring between TFIIE and TFIIH during transcription. Our work revealed an unexpected dynamic process during which TFIIE act as key factors to recruit and position the kinase module of TFIIH within the preinitiation complex. Strikingly, TTD-related mutations in either TFIIH or TFIIE similarly disrupt this early transcriptional process, which could explain why alterations in different transcription factors can lead to the same clinical syndrome.

Annonce de séminaire


Vendredi 16 Novembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Laurent BARTHOLIN

CRCL, Lyon

The obnoxious faces of TGFbeta in pancreatic cancer

Invité par Rémi Mounier

Abstract
The Transforming growth factor beta (TGFB) is a pleiotropic secreted factor with many roles during embryonic and adult life. In cancer, it behaves either as a tumor suppressor or a tumor promoter. To understand this functional duality, our lab have been using as a model Pancreatic Ductal Adenocarcinoma (PDAC), one of the most aggressive tumor, which is expected to become the second cancer-related cause of death by 2030 (after lung cancer). Our work is focused on the oncogenic properties of TGFB with the final goal to specifically target them by developing innovating therapeutics. During this presentation, I will present our work to understand the TGFB oncogenic effects at the molecular (a “new” oncogenic signaling pathway), cellular (effect on differentiation of pancreatic acinar cells), organ (interaction between PDAC cells and nerves invading the tumor) and whole body levels (interaction with muscle).


Décembre 2018

Vendredi 14 Décembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Fabien LE GRAND

Centre de Recherche en Myologie, Paris

Signaling pathways in muscle tissue regeneration

Invité par Laurent Schaeffer

Abstract
The development and repair of complex metazoan tissues are coordinated by a startlingly small number of evolutionarily conserved signaling pathways. These signals can act in parallel but often function as an integrated hyper-network. Our research aims at understanding the signaling nodes defining this molecular circuitry and the biological significance of pathway cross-talk, using skeletal muscle as a fitting model. Regeneration of the adult muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). We previously demonstrated that numerous WNT molecules are secreted in the local milieu during muscle regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP (1). To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific mutations (2, 3). Mechanistically, we observed that Wnt/ß-catenin signaling orchestrate the cytoplasmic relocalisation of the H3K9 methyltransferase SETDB1 during differentiation (4). We further investigated how Wnt/ß-catenin signaling is connected to Bone morphogenetic protein (BMP) and Transforming growth factor beta (TGF-ß) pathways. Recent work in our lab consisted in dissecting the impact on these pathways on MuSC return to the niche and fusion, respectively. Nevertheless, our understanding of the cells that compose skeletal muscle tissue is limited and molecular definitions of the principal cell types are lacking. This hinders our capacity to decipher signal integration and reciprocity between cells. We thus used a novel combined approach of single-cell RNA-sequencing and mass cytometry and precisely mapped 10 different cell types in adult mouse skeletal muscle, including two previously unidentified populations (5). This cartography yields crucial insights into muscle-resident cell type identities and will be exploited to build a muscle connectome.


Mercredi 19 Décembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Bert Blaauw

Venetian Insitute of Molecular Medicine

The role of mTORC1 signaling in adult skeletal muscle

Invité par Laurent Schaeffer

Abstract
It is well established that mTORC1 signaling is key modulator of skeletal muscle mass and function. Surprisingly, despite the fact that skeletal muscle undergoes major changes in size and contractility in numerous diseases, no genetic loss-of-function model has been generated to determine the effect of inducible deletion of mTORC1 in adult skeletal muscle. Here we generated inducible, muscle-specific Raptor and mTOR k.o. mice. Interestingly, we do not observe a change in muscle size or contractile properties one month after deletion. However, treating these mice with the mTOR-inhibitor rapamycin is sufficient to induce a very rapid and marked myopathy, suggesting that little residual mTOR signaling can maintain muscle homeostasis in adult muscle. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by muscle dysfunction, regeneration, glycogen accumulation and mitochondrial dysfunction and block in autophagy. Unexpectedly, one of the best markers of reduced mTOR signaling in muscle fibers is the appearance of denervated fibers. Both muscle-specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce the appearance of numerous NCAM-positive fibers, muscle fibrillation, and neuromuscular junction fragmentation. Taken together, these results link one of the most important anabolic pathways in skeletal muscle fibers to the maintenance of the NMJ.


Octobre 2018

Mardi 9 Octobre à 11:00 – Salle RBC 301

Hélène PUCCIO

Department of Translational Medecine and Neurogenetics, IGBMC, Strasbourg

Advances in Friedreich Ataxia: understanding the function of frataxin and developing therapeutic approaches

Invité par Laurent Schaeffer

Abstract
Friedreich’s ataxia (FA), the most common autosomal recessive ataxia, is characterized by a sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy and increase incidence of diabetes. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Fe-S clusters are ancient and essential cofactors that participate in a number of cellular processes ranging from mitochondrial respiration to DNA metabolism. In eukaryotes, de novo Fe-S biogenesis takes place within mitochondria and relies on proteins that are highly conserved from bacteria to humans. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in individuals with FA. To date, no treatment exists for stopping or slowing FA disease.
Over the past years, we have generated cellular and mouse models that reproduce important progressive pathological and biochemical features of the human disease, including cardiac hypertrophy, mixed cerebellar and sensory ataxia, Fe-S enzyme deficiency, and intramitochondrial iron accumulation. These models have enabled us to demonstrate that Fe-S deficit is a primary event of the disease leading to iron metabolism deregulation through the activation of the iron-regulatory protein, IRP1. These models are excellent models for deciphering the physiopathology of the disease and for testing pre-clinical therapeutic protocols. The latest advances in understanding the pathophysiology will be discussed, with a particular emphasis on new neurological models that are being developed as well as therapeutic approaches.


Mercredi 10 Octobre à 14:00 – Salle des Pas Perdus – 1er étage – Faculté de Médecine Lyon Est

Juliette GODIN

Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg

Pleiotropic activities of the (atypical ?) kinesin KIF21B during cortical development

Invité par Julien Courchet

Abstract
Cortical development progresses through concurrent steps, including neural proliferation, migration and differentiation, that rely on dynamic cell shape remodeling which largely depends on the tight regulation of the microtubules (MT) cytoskeleton. Mutations in tubulin, MT associated proteins or motors have been linked to several neurodevelopmental disorders including malformation of cortical development (MCDs), affecting 2,5% of the world population. Here we identified KIF21B gene as a major locus of human neurodevelopmental disorder. We identified 4 de novo variants in KIF21B gene in patients with intellectual disabilities associated with several brain malformations, including microcephaly, corpus callosum agenesis or facial dimorphism. In support of the pathogenic potential of the discovered alleles, expression of KIF21B variant in mice using in utero electroporation or in zebrafish embryos recapitulated key neurodevelopmental phenotypes, namely migration and microcephaly. In addition, longitudinal neuroanatomical analysis of Kif21b KO model showed strong morphological defects starting prenatally and worsening with time. Finally, we demonstrated that Kif21b regulates migration of projection neurons through the tight control of locomotion and neural shape. Although its motility is dispensable, the regulatory function cytoskeleton dynamics is essential for neuronal migration. Altogether, our data represent an important step to delineate the mechanisms involving KIF21B-mediated MT dynamics and trafficking in the context of brain development.

Annonce de séminaire


Jeudi 11 Octobre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Belinda COWLING

Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg

Myostatin – A novel biomarker for Dnm2 therapy in Myotubular Myopathy mice

Invité par Vincent Gache

Abstract
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, myotubular myopathy (X-linked CNM), is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We have shown that antisense oligonucleotide (ASO) mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1 in mice, providing an attractive therapeutic strategy for this disease. We are now investigating blood-based biomarkers that can be used to monitor disease state and rescue in myotubular myopathy mice. Myostatin is a protein produced and released by myocytes, which acts in an autocrine function to inhibit muscle growth and differentiation. Our results suggest myostatin pathway is ‘turned down’ at the mRNA level in muscle biopsies, leading to low levels of circulating and endogenous muscle myostatin in plasma. We have generated preliminary data suggesting ASO-mediated DNM2 reduction results in an increase in circulating myostatin. With clinical trials for myotubular myopathy currently in progress, identification of novel blood-based biomarkers such as myostatin may allow for monitoring of treatment efficacy in patients.

Annonce de séminaire


Vendredi 12 Octobre à 11:00 – Salle Hermann – 1er étage – Faculté de Médecine Lyon Est

Luisa COCHELLA

Research Institute of Molecular Pathology (IMP), Vienna, Austria

Roles of micro RNAs in animal development: lessons from C.elegans

Invité par Florence Solari

Abstract
One of the main goals of developmental biology is to understand how the different cell types that constitute a multicellular organism are specified during its development. Luisa Cochella is a young PI (awarded for both ERC starting Grant and EMBO Young investigator program) who is currently exploring the different mechanisms of gene expression regulation that control this process. Her lab investigates how the transcriptional history of a cell influences its fate as well as how post- transcriptional mechanisms contribute to the diversification of the genetic programs that control cell fate. Luisa is more specifically interested in both neuronal and muscle differentiation

Annonce de séminaire


Mardi 30 Octobre à 11:00 – Salle Hermann – 1er étage – Faculté de Médecine Lyon Est

Huating WANG

The Chinese University of Hong Kong, Hong Kong, China

Functional investigation of LncRNAs and enhancers in skeletal muscle stem cells

Invité par Bénédicte Chazaud

Abstract
Previously, the majority of the human genome was thought to be « junk » DNA with no functional purpose. Over the past decade, evidence from numerous high-throughput genomic platforms reveals that even though less than 2% of the mammalian genome encodes proteins, a significant fraction can be transcribed into different complex families of non-coding RNAs (ncRNAs). Growing evidence supports that ncRNAs have fundamental roles as regulators of genomic output. Among various types of ncRNAs, microRNAs have dominated the current literature. Other groups, however, such as long ncRNAs (lncRNAs, >200nt), have been largely under explored.
Huating Wang’s lab is currently interested in studying the functional roles of long non-coding RNAs (lncRNAs and enhancers) in regulating gene expression in skeletal muscle stem cells and muscle regeneration.

Annonce de séminaire


Septembre 2018

Mardi 11 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Sonia Garel

Institut de Biologie de l’École Normale Supérieure, Paris

Microglia and prenatal inflammation in early cortical wiring

Invité par Jean-Louis Bessereau

Abstract

Prenatal inflammation and dysfunction of microglia, the brain resident macrophages, have both been associated with the etiology of several neuropsychiatric disorders, including schizophrenia and autism spectrum disorders. Consistently, microglia were shown to regulate neurogenesis, synaptic remodeling and maturation at postnatal stages. However, microglia invade the brain during mid-embryogenesis and could thus exert earlier prenatal and perinatal roles during normal and pathological brain wiring. Here we show that embryonic microglia, which display a transient uneven distribution, regulate the wiring of forebrain circuits. By taking advantage of multiple mouse models, including cell-depletion approaches, we found that perturbing microglia activity affects the development of neocortical inhibitory interneurons, which constitute main actors in neuropsychiatric diseases. In particular, absence, prenatal inflammation or functional perturbation of microglia affects the timely positioning of specific subsets of interneurons as well as their subsequent functional integration in the neocortex. We furthermore found that responses of microglia to environmental signals, including the ones from the microbiome, are sexually dimorphic in males and females. This remarkable finding has major implications for our comprehension of sexual biases in the occurrence of microglia-related diseases, such as the prevalence in males of neurodevelopmental disorders. Our work reveals key roles for immune cells during the normal assembly of cortical circuits and provides novel insights onto how microglia dysfunction or immune risks lead to pathological brain wiring.

Annonce de séminaire


Mercredi 19 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Yasushi Okamura

Graduate School of Medicine, Osaka University Suita

Coupling from electric signal to lipid signal; voltage-sensing phosphoinositide phosphatase

Invité par Vincent Jacquemond

Résumé

Biological membranes have dual roles in cell signaling: insulator for electrical signal by transfer of ion across membrane as well as the place for metabolism for production of lipid mediators such as arachidonic acids or phosphophositides. These two signals interact with each other through changes of ion concentration, mainly intracellular calcium ions, by the concerted activities of ion channels, transporters and GPCRs. There is a rare case where single membrane proteins directly link between electrical signal and lipid-mediated cell signaling. Voltage-sensing phosphatase consists of the ion channel like voltage sensor and PTEN-like phosphoinositide enzyme. In VSP, single voltage sensor regulates the downstream enzyme and the phosphoinositide phosphatase activity is activated by membrane depolarization leading to depletion of mainly PI(4,5)P2. Substrate specificity of VSP is more broad than PTEN; VSP shows both of 3-phosphatase activity and 5-phosphatase activity unlike PTEN which shows the rigid selectivity toward 3-phosphate of the inositol ring of PI(3,4,5)P3 and PI(3,4)P2. However, the key question how transmembrane voltage sensor regulates the cytoplasmic enzyme has remained unanswered, mainly because a method of detecting structural change in the cytoplasmic region has been limited. We have recently applied a method of genetical incorporation of fluorescent unnatural amino acid, Anap, to the cytoplasmic region of Ci-VSP (sea squirt Ciona intestinalis VSP) which was expressed in Xenopus oocyte. This method enables detection of fine structural change reported by fluorescence intensitiy without perturbing the local protein structure. Voltage-dependent fluorescence change of Anap showed two bidirectional changes along the voltage, decrease at low membrane depolarization and increase at higher depolarization, suggesting that the structure of the cytoplasmic region takes multiple conformations. By applying the method to different constructs of Ci-VSP with altered enzyme activity, we obtained evidence that the enzyme takes at least two activated states with distinct magnitude of enzyme activity. Given that voltage sensor of Ci-VSP takes multiple states during activation, it will be intriguing to see in the future how individual enzyme states correlate with states of the voltage sensor.

Annonce de séminaire


Lundi 24 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Edgar Gomes

Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

Mechanisms of nuclear positioning during myofiber formation

Invité par Bénédicte Chazaud

Résumé

Connecting the nucleus to the cytoskeleton is relevant for multiple cellular processes and disruption of these connections result in multiple pathologies. Nuclear positioning within cell cytoplasm requires de connection between nucleus and the cytoskeleton. We are interesting to understand the processes involved in these connections and the role for nuclear positioning in cell function. We study cell migration and skeletal myofiber formation which required the connection between the nucleus and the cytoskeleton and precise nuclear positioning. We use different molecular and cellular approaches in combination with time-lapse imaging analysis to address these questions.

Annonce de séminaire


Jeudi 27 Septembre à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est

Rashmi KOTHARY

Centre for Neuromuscular Disease University of Ottawa

Spinal Muscular Atrophy: a multi-organ disease

Invité par Patrick Lomonte

Abstract

Spinal Muscular Atrophy was characterized in the late 1800s but it was almost 100 years later that the genetic cause was identified as a mutation in the human SMN1 gene. While humans do have two genes that code for SMN, SMN2 only produces 10% protein when compared to SMN1. Early work with mouse models was complicated by the fact that mice only have the one Smn gene which when mutated results in preimplantation lethality. This problem was solved by the development of a mouse model incorporating human SMN2 gene, which was for years the only viable mouse model. Now, there are over a hundred mouse models available that have served to inform our understanding of pathogenesis in SMA.
Classically, SMA is described as a motor neuron disease; however, SMN is expressed ubiquitously throughout the body. In fact, SMA is emerging to be a multi-organ disease with SMN depletion having impacts on many tissues in the body. Subcutaneous administration of available treatments may address these affected organs better than intrathecal administration. Also, systemic gene therapies that are currently under development may help repair function in these other organs.
Dr. Kothary will present on the work in his laboratory on the multi-organ nature of SMA. Defects in various tissues will be discussed.

Annonce de séminaire


Juin 2018

Vendredi 29 Juin à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est – 3ème étage

Laure STROCHLIC

Institut de Myologie – Centre de Recherche en Myologie, Sorbonne Université, INSERM AIM UMRS974, Paris

Regulation of neuromuscular connectivity by Wnt signaling from signaling molecules to therapeutic strategies

Invité par Rémi Mounier

Résumé

The development and maintenance of the neuromuscular connectivity relies on a temporally fine-tuned balance of distinct bi-directional communication between motor neurons and their muscle targets. Disruption of this communication leads to structural and functional defects that affect the motor function and causes severe neuromuscular pathologies. Wnt signaling participates in various developmental mechanisms such as migration, axonal guidance or synaptogenesis. But how the Wnt signaling network could regulate neuromuscular connectivity and how it could affect motor function is unknown. In this presentation, I will provide data using Wnts gain or loss of function studies in cell culture or in mice showing that distinct branches of Wnt signaling, acting in part via the muscle-specific kinase MuSK regulate several key aspects of the formation and maintenance of the neuromuscular synapse including pre and postsynaptic differentiation/stabilization, retrograde control of motor axon outgrowth and synapse-specific gene expression. I will also present evidence showing that the pharmacological modulation of Wnt signaling in a pathological context could be used as a therapeutic strategy to counteract neuromuscular junction (NMJ)- associated disorders. Overall, our results provide novel insights into the mechanisms by which synaptic diffusible cues act to prevent NMJ dysfunction, muscle weakness and disease.

Dans cette présentation, je fournirai des données, utilisant des approches expérimentales in vitro et in vivo chez la souris, qui montrent le rôle émergent de la signalisation Wnt dans la régulation de la connectivité neuromusculaire dans un contexte physiologique et pathologique.

Annonce de séminaire


Mai 2018

Vendredi 4 Mai à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Helge AMTHOR

Université de Versailles – Paris Saclay Laboratoire U1179 UVSQ – INSERM

BMP signaling controls limb muscle development and maintenance

Invité par Laurent Schaeffer

Résumé
Bone morphogenetic proteins (BMPs) regulate the activity of skeletal muscle precursors as well as the trophic state of differentiated muscle. Here, the role of BMP signaling was explored at different stages of limb muscle development by overexpressing an inhibitory Smad protein (Smad6) to abrogate the BMP signaling cascade at cell autonomous level. Overexpression of Smad6 in limb muscle precursors during development (crossing Rosa26-Lox-Stop-Lox-Smad6-IRES-GFP mice, termed RS6, with Lbx1Cre/+ transgenic mice) disturbed limb muscle myogenesis: early myogenic markers Pax3 and MyoD were strongly downregulated, fetal limb muscles were smaller, consisted of fewer myofibers and displayed a disturbed muscle patterning. Overexpression of Smad6 in postnatal muscle precursors (using RS6: Pax7CreERT2/+ mice) caused decreased cell proliferation resulting in smaller myofibers containing less myonuclei and in decreased generation of satellite cells. Overexpression of Smad6 in differentiated muscle resulted in a different phenotype (using RS6:HSA-Cre mice): limb muscles were only modestly smaller, however, consisted of fewer but larger myofibers with increased myonuclear number. Overexpression of the BMP antagonist Noggin in adult muscle (loss-of-function) resulted in muscle fiber atrophy, whereas overexpression of the BMP receptor Alk3 (gain-of-function) caused muscle fiber hypertrophy. These latter effects were likely muscle precursor independent, as overexpression of Smad6 in differentiated fibers (using RS6:Pax7CreERT2/+ mice) had no effect on satellite cell number and muscle size in the adult. In conclusion, the role of BMP signaling in skeletal muscle is stage and context specific.

Annonce de séminaire


Mercredi 16 Mai à 11:00 – Salle des Pas Perdus, 1er étage

Vanina ROMANELLO

Venetian Institute of Molecular Medicine, Padova

The role of the myokine FGF21 in skeletal muscle homeostasis

Invité par Rémi Mounier

Résumé
Skeletal muscle is a major site of metabolic activity and the most abundant tissue in the human body accounting for almost 40% of the total body mass. It is a plastic tissue that adapts to changes in exercise, nutrition and hormones, which also induces the release of myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine and endocrine effects, explaining how muscles regulate metabolic homeostasis in other tissues. These systemic effects help to explain why physical activity, and thereby muscle recruitment, elicits several beneficial effects in many different diseases. Indeed, exercise preserves and ameliorates mitochondrial function and muscle metabolism, thereby affecting the release of myokines and metabolites that systemically counteract organ deterioration. We have recently proposed an interplay between the myokine Fgf21 and the mitochondrial quality control pathways that greatly contributes to a pro-senescence metabolic shift. However, even though the myokine field is exponentially increasing, little is known about their role in muscle homeostasis.

Annonce de séminaire


Jeudi 31 Mai à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Robert J. Johnston

Johns Hopkins University, Baltimore, USA

Stochastic gene expression and nuclear architecture in fly eyes and human retinal organoids

Invité par Thomas Boulin

Résumé
A central challenge in developmental neurobiology is to understand how the myriad types of neurons in the human nervous system are generated. Stochastic gene expression mechanisms are crucial to differentiate neuronal subtypes and expand function. During stochastic fate specification, individual neurons randomly choose between different fates, resulting in unique patterns but consistent proportions of cell types among genetically identical organisms. My lab studies the stochastic mechanisms that specify the color-detecting photoreceptors in the fly and human retina. Fruit flies have a well-characterized retina and an abundance of genetic tools that enable molecular analyses of gene regulatory mechanisms. To overcome the challenges associated with human studies, we have developed a human retinal organoid system that recapitulates retinal development and photoreceptor specification. With these systems, we are interrogating how DNA elements, trans factors, and chromatin architecture control random on/off gene expression. Our molecular approaches are complemented by quantitative genetics to determine how natural variation in the genome impacts gene expression and photoreceptor specification. Finally, we conduct behavioral and functional assays to measure differences in color perception when photoreceptor fates are altered. By studying highly divergent organisms from multiple angles, we aim to define the unifying principles underlying stochastic fate specification during nervous system development.

Annonce de séminaire


Avril 2018

Vendredi 6 Avril à 11:00 – Salle des Pas Perdus, 1er étage

Athanassia SOTIROPOULOS

Institut Cochin, Paris

Role of Srf transcription factor and F-actin scaffold in muscle stem cell fusion

Invité par Rémi Mounier

Résumé
Our team is interested on how signaling pathways control of adult skeletal muscle plasticity. In the past years, we focused our attention on Srf transcription factor which is one of the three master genes that controls myogenesis in Caenorhabditis elegans, together with MyoD and HAND. We investigated the role of Srf in two cellular compartments of mouse skeletal muscle (myofibers and adult muscle stem cells) upon different perturbation of muscle homeostasis (hypertrophy, atrophy, regeneration). In the present seminar, I will summarize our findings concerning the role of Srf in myofibers to control muscle mass and I will present recent data identifying Srf as a master regulator of muscle stem cell fusion and demonstrating the implication of F-actin architecture in this process.

Seminar announcement


Mars 2018

Vendredi 16 mars à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Cécile MARTINAT

INSERM/UEVE UMR861, I-STEM, AFM

Human pluripotent stem cells for the study and treatment of neuromuscular diseases : myth or reality ?

Résumé
Neuromuscular diseases correspond to a vast group of diseases that perturbs the function of the skeletal muscles by affecting motoneurons, muscles and/or NMJs. To date, no efficient curative treatments have been identified for NMD. Progresses towards identification of new treatment have been hampered by the incomprehension of disease pathogenesis, particularly in early phases, as well as the availability of relevant screening tools. Disease-specific human pluripotent stem cells, from embryonic origin or derived from reprogramming somatic cells, offer the unique opportunity to have access to a large spectrum of disease-specific cell models. Due to their ability of self-renewal and differentiation into various tissues affected in each pathological condition, the development of these human disease-specific pluripotent stem cells provide new insights in pathological mechanisms implicated in human diseases for which, accessing homogenous affected tissues is often challenging. Validating this concept, we previously demonstrated that human pluripotent stem cells and derivatives which, express the causal mutation implicated in the Myotonic Dystrophy type 1 (DM1), offer pertinent disease-cell models, applicable for a wide systemic analysis ranging from mechanistic studies to therapeutic screening. Thus, we identified, through a genome-wide analysis, two early developmental molecular involved both in myogenesis as well as in neurite formation and establishment of neuromuscular connections. These neuropathological mechanisms may bear clinical significance as related to the functional alteration of neuromuscular connections associated with DM1. In parallel to these functional pathological studies, we also demonstrated the pertinence of this new disease-specific cell model to identify new therapeutic strategies. Thus, our results identified the possibility to repurposing metformin, the most commonly prescribed drug for type 2 diabetes, for DM1 leading to a phase 2 clinical trial that is actually ongoing.
We are now extending our approach to another incurable neuromuscular disease, spinal muscular atrophy (SMA). This disease, considered as the leading genetic cause of infant death, is due to mutations or deletions in the « Survival of Motor Neuron » gene, SMN1, which results in low levels of the expressed SMN protein. Despite this ubiquitous SMN expression, the pathology is characterized by degeneration of spinal Motor neurons whereas other neuronal types are relatively preserved suggesting that spinal motor neurons specific features control this differential sensitivity. Based on our recent development allowing the efficient and robust conversion of human pluripotent stem cells into affected spinal motor neurons and non- affected cranial motor neurons, our objective is to deepen the mechanisms involved in the specific degeneration of spinal motor neurons in SMA as well as the mis communication of these neurons with their muscular target.

Annonce de séminaire


Lundi 19 Mars à 10:00 – Amphi 4 – 4e étage

Christoph Hoefer, M. Sc.

Senior Business Development Manager ; Life Sciences Solutions, Cell Biology, ThermoFisherScientific

Séminaire Technique : Travailler avec des iPSC (induced Pluripotente Stem Cell)

Résumé
Les cellules souches pluripotentes humaines (iPSC) sont des outils puissants pour la recherche en biologie du développement, la médecine régénérative et l’étude des pathologies humaines. Les données obtenues à partir de modèles physiologiques in vitro amélioreront grandement notre compréhension des processus biologiques. Dans cette présentation, j’aborderai les principaux défis rencontrés dans la mise en place des cellules souches pluripotentes au sein d’un laboratoire et les améliorations récentes apportées à la construction de modèles pour les maladies humaines, telles que la reprogrammation, l’expansion, la transfection, la préservation et la différenciation efficace de iPSC, ainsi que les options de modifications génomiques.

Annonce de séminaire


Vendredi 2 Mars à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Nicolas PLACE

Institute of sport Sciences, University of Lausanne

Skeletal muscle adaptations to exercise : a translational approach

Invité par Julien Gondin

Résumé
The amount of force skeletal muscles can produce depends on their contractile history. For instance, repeated contractions generally lead to reduced muscle force generating capacity, namely muscle fatigue. Although muscle fatigue has been the focus of many works in the last 100 years, the underlying mechanisms remain elusive. In this presentation, special emphasis will be given to the role of Ca2+ handling as a key regulator of (i) muscle weakness and (ii) beneficial adaptations observed after high intensity interval training. In particular, the potential role of the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor type 1, will be discussed.

Annonce de séminaire


Lundi 5 Mars à 14:00 – Salle des Conférences – Médiathèque Paul Zech

Julien OCHALA

Faculty of Life Sciences & Medicine, King’s College, London

Actinopathies : From Mutations to Treatment

Invité par Laurent SCHAEFFER

Résumé
Actinopathies are genetically and clinically heterogeneous disorders mainly characterized by generalized muscle weakness. The understanding of this group of disorders has advanced in recent years through the identification of the causative mutations in the gene encoding one of the major proteins of the basic contractile unit of skeletal muscle, i.e., actin. In the present seminar, I will present (i) how these gene mutations lead to generalized muscle weakness and (ii) the advances regarding potential therapies.

Annonce de séminaire


Février 2018

Vendredi 9 Février à 14:00 – Salle des Conférences – Médiathèque Paul Zech

Norbert WEISS

Institute of Organic Chemistry and Biochemistry, Prague

Trafficking of T-type calcium channels in health and disease

Invité par Vincent JACQUEMOND

Résumé
T-type calcium channels are key contributors to neuronal physiology where they shape electrical activity of nerve cells and contribute to the release of neurotransmitters. Alteration of T-type channel expression has been causally linked to a number of pathological conditions including neuropathic pain and absence seizure activity. Although a number of signaling pathways regulating the activity of T-type calcium channels have been reported, the molecular machinery and signaling molecules controlling the trafficking and expression of the channel protein at the plasma membrane remain largely unknown. I will present some of the basic mechanisms recently identified controlling the physiological trafficking of T-type channels, and illustrate how metabolic defects or congenital mutations can disturb this trafficking machinery and eventually leading to disease conditions.

Annonce de séminaire


Janvier 2018

Mardi 30 janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Isabelle JANOUEIX

Institut Curie – Inserm U8330, Paris

Understanding neuroblastoma biology through the analysis of its genetic and epigenetic landscapes

Invité par Valérie Castellani

Résumé
Neuroblastoma is an embryonal neoplasm arising from the peripheral nervous system that accounts for 15% of cancer deaths in childhood. It is an enigmatic tumor presenting with a great genetic and clinical heterogeneity, both in terms of presentation and outcome.
The characterization of the genetic alterations observed in neuroblastoma led to the identification of major players of neuroblastoma oncogenesis that has considerably improved our understanding of the biology of this pediatric cancer. More recently, the analysis of the super-enhancer landscape allowed to decipher the core regulatory circuitries controlling the gene expression program of neuroblastoma. Distinct transcription factor networks predicate different tumor identities, corresponding to sympathetic noradrenergic or mesenchymal/neural-crest cell like identities. Cells of mesenchymal identity are more resistant to chemotherapeutic agents. Moreover, some neuroblastoma cells exhibit plasticity and are able to shift between the NCC-like and noradrenergic identities.
The understanding of cell identity, heterogeneity and plasticity in neuroblastoma has strong implications with respect to the development of new therapeutic strategies to eradicate tumor cells in neuroblastoma patients.

Annonce de séminaire


Mercredi 10 janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Justin FALLON

Brown University, Providence, RI

MuSK as a BMP co-receptor

Invité par Laurent Schaeffer


Décembre 2017

Vendredi 1er Décembre à 11:00 – Amphithéâtre CNRS

Chantal Thibert

Institute for Advanced Biosciences, Université Grenoble Alpes

The tumor suppressor LKB1 controls cell fate through pyruvate-alanine transamination

Invité par Julien Courchet

Résumé
The tumor suppressor LKB1 (also named STK11) codes for a serine/threonine kinase. LKB1 acts as a key regulator of cell polarity as well as energy metabolism partly through the activation of the AMP-activated protein kinase (AMPK), a sensor that adapts energy supply to the nutrient demands of cells facing situations of metabolic stress.
To determine if Lkb1 exerts a coordinated regulation of energy metabolism and cell polarity, we deleted the Lkb1 gene in polarized cells and explored the metabolic consequences. In particular, we generated spatio-temporal ablation of Lkb1 in a subpopulation of mouse embryonic multipotent neural crest cells (NCC) that originate from the neural tube and give rise to a broad range of derivatives including most of the face, the melanocytes, the peripheral nerves and the enteric nervous system (ENS). Mutant mice exhibited craniofacial malformations, hypopigmentation, intestinal pseudo-obstruction and hindlimb paralysis. Further phenotypic characterization revealed that LKB1 is required for the differentiation and maintenance of two NCC-derivatives, Schwann cells and the ENS. Using a model of neural crest stem cell line, we demonstrated that Lkb1 is key for neural crest-derived glial commitment. Mechanistically, Lkb1 loss led to an increase of alanine and glutamate levels and inhibition of pyruvate-alanine transamination rescued glial differentiation of Lkb1-null NCC, in a mTOR dependent manner. Furthermore, AICAR, an analogue of AMP, rescued glial differentiation of Lkb1-deficient NCC and corrected the Schwann cells and ENS phenotypes of Lkb1 mutant mice.
Altogether, these findings highlight the central role of Lkb1 during neural crest cell lineage and uncovered a link between Lkb1-mediated pyruvate-alanine cycling and glial commitment. These results provide also new insights for the understanding of metabolic events that contribute to the formation of LKB1-deficient malignancies.

Annonce de séminaire


Novembre 2017

Vendredi 10 Novembre à 11:00 – Amphithéâtre CNRS

Michalis Averof

Institut de Génomique Fonctionnelle de Lyon (IGFL).

Live imaging of regenerating legs: cell dynamics and progenitors

Invité par Rémi Mounier

Résumé
Regeneration is a complex and dynamic process, mobilising diverse cell types and remodelling tissues over a long time period. Compared with embryonic development, it is less genetically tractable and less accessible for direct observation. I will describe our recent efforts to establish a small crustacean, Parhyale hawaiensis, as an experimental model for studying regeneration. Using transgenic markers and live imaging we are starting to describe the cell behaviours and progenitors that underpin limb regeneration. We find that crustacean limb regeneration relies lineage-committed progenitor cells: muscles derive from satellite-like stem cells, whereas epidermis regenerates from existing epidermal cells.

Annonce de séminaire


Octobre 2017

Jeudi 12 Octobre à 11:00 – Salle Fontanes, Darwin D

Damaris Lorenzo

University of North Carolina at Chapel Hill

Ankyrin-B and beta-II spectrin in axonal transport and brain connectivity

Invité par Thomas Boulin

Résumé
The formation, targeting, and maintenance of axon and dendrites are critical for proper brain development and synaptic function. Deficits in synapse establishment and maturation can lead to neurodevelopmental, neurodegenerative, and psychiatric disorders. The neuronal cytoskeleton regulates the architecture and dynamics of synaptic processes by providing structural support and the tracks for motor protein-based synaptic transport. The latter is particularly important for the establishment of long axonal projections, which requires coordinated long-range organelle transport. The membrane associated adaptor ankyrin-B (AnkB) promotes fast axonal transport and elongation by coupling dynactin to multiple organelles through binding to phosphatidylinositol 3-phosphate lipids in these cargos. Additionally, AnkB directly binds βII-spectrin, which, in turn, controls the formation of a ring-shaped membrane periodic skeleton (MPS) in axons and mature dendrites. Interestingly, βII-spectrin also associates with molecular motors. I will show that AnkB and βII-spectrin are key elements in independent and overlapping pathways responsible for the transport of synaptic cargo and other organelles, and are essential for establishing proper brain structural and functional connectivity.

Annonce de séminaire


Mai 2017

Vendredi 12 mai à 11:00 – Amphithéâtre CNRS

Andre Brown

MRC London Institute of Medical Sciences – Imperial College, London

Syntax in C. elegans locomotion

Invité par Thomas Boulin

Résumé
Behaviour is a striking phenotype and often one of the first things we notice about an animal. Broadly speaking, we are interested in understanding how genes affect behaviour, but despite rapid advances in technology for sequencing and engineering genomes, it is still a challenge to associate particular genes with heritable behavioural differences because behaviour is time consuming to measure and difficult to quantify. We are using automated imaging to record the behaviour of freely moving nematode worms and developing new analysis methods to extract relevant features. I will discuss unsupervised methods to quantify behavioural repertoires, and how making connections to language processing and data compression can give insight into the structure of behaviour. Finally I will show how these new representations can advance the study of behavioural genetics and phenotypic drug screening.

Annonce de séminaire


Mercredi 17 mai à 14:00 – Salle Guillermond – Bât. L’Herbier

Hélène CASTEL

Normandie Rouen University / Inserm 1239 – Équipe Astrocyte and Vascular Niche

Cancer and Cancer treatments on cognition: A major translational impact of the preclinical research

Invité par Virginie DESESTRET

Résumé
Co-head Cancer and Neurosciences axis Northwest canceropole, Cancer and cognition platform; ICCTF member (editing of preclinical research guidelines).
The emergence of a new field in oncology addressing cognitive deficits in cancer patients is justified by the existence of deficits in memory, concentration and attention, as well as executive functions before, during and after treatments, symptoms often referring to the “chemofog” or “cancerfog”. Our work mainly involves research and clinical groups of Normandie developing programs in patients and animal models, to improve our understanding of the impact of cancer and its treatments on cognitive functions. Two main examples of these translational studies we participated on can be exposed:
The first Cog-Age clinical study (Pr F. Joly, Baclesse Caen) showed that cognitive decline can be detected 6 months after chemotherapy in breast cancer elderly patients. In a mirror study, chemotherapy administration in young and elderly mice resulted in a change in behavioral flexibility and alteration of neuron precursor proliferation in the hippocampal dentate gyrus. We were thus able to conclude that age-related cognitive decline is accentuated by chemotherapy, providing basis for questioning the place of adjuvant chemotherapy in this elderly patient population. The second clinical study COG-ANGIO (Pr Joly) demonstrated that antiangiogenics exert a direct negative impact on cognitive functions and fatigue in kidney cancer patients. In mice, the anti-angiogenic mTOR inhibitor everolimus did not alter cognitive functions but led to weight loss and modification of cell metabolism in brain regions involved in sleep/wake cycle or food intake, likely connected to fatigue. On the other hand, immunoneutralizing VEGF (Genentech-Roche, MTA) impaired spatial learning performance and neuronal activity of CA3 hippocampus neurons. These data suggest that a careful and systematic evaluation of targeted cancer therapies on cognitive functions in preclinical models may constitute a strategy of prevention by selection of treatments exhibiting minimum brain co-morbidities.
Together, this translational program is developed within the National Cancer and Cognition Platform (CNO/Ligue Nationale contre le cancer), with the aim to collaborate in a structured way with French oncology groups, research teams as well as pharmaceutical industry, by providing preclinical models and guidance on standard operating procedures for ancillary or future studies in identified population at risk.

Annonce de séminaire


Mars 2017

Vendredi 31 Mars à 11:00 – Salle FONTANNES – Bât. Darwin D RdC

Kei Sakamoto

Institut des Nestlé Institute of Health Sciences SA, Lausanne.

Key signaling players in the control of hepatic gluconeogenesis — AMPK or other AMPK-related/AMP-regulated enzymes ?

Invité par Rémi Mounier

Résumé
Hepatic glucose production is a key physiologic process that ensures energy balance for glucose-dependent organs/cells such as brain. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type 2 diabetes. LKB1, originally identified as a tumor suppressor protein, is currently thought as a critical regulator of cellular metabolism and growth by controlling the activity of AMP-activated protein kinase (AMPK) and also 12 other kinases that are closely related to AMPK. Among those AMPK-related kinases, we have recently identified that Salt-Inducible Kinase (SIK) plays an important role as a gluconeogenic gatekeeper in the liver.
Metformin exerts its major effect via inhibition of hepatic glucose production. This is thought to be mediated through decreased hepatic energy charge (i.e. increasing AMP/ATP ratio) via inhibition of mitochondrial respiration. The long-standing belief that 5’-adenosine monophosphate (AMP)-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged in experiments using mice lacking hepatic AMPK. I will discuss our recent data demonstrating AMP-mediated allosteric inhibition of an enzyme involved in gluconeogenesis plays a key role in acute glucose-lowering effect of metformin.

Annonce de séminaire


Janvier 2017

Jeudi 12 Janvier à 14:00 – Amphithéâtre CNRS

Alexandre Pattyn

Institut des Neurosciences de Montpellier, INSERM U1051. France.

Heterogeneous precursor populations underlie developmental plasticity of the dorsal root ganglia

Invité par Valérie Castellani

Résumé
Although a variety of primary sensory neurons are implicated in the detection and transmission of different sensory modalities, how they arise during development remains poorly understood. The process of neuronal specification is the acquisition of definitive phenotypic characteristics for a given subclass of neurons during embryonic development. This acquisition can be divided into several interdependent and sequential phases, from the time point when progenitor cells exit the cell cycle toward the newly formed and perfectly differentiated neuron. Using mouse genetics, Alexandre demonstrated that transcriptions factors of Maf and Zeb families control the specification and differentiation of specific sensory neuron sub-types. His work contributed to uncover the complex developmental sequence ensuring the formation of the peripheral sensory system and to highlight the progenitor diversity that underlies the developmental plasticity of sensory neuron generation.

Annonce de séminaire


Jeudi 19 Janvier à 11:00 – Salle FONTANNES – Bât. Darwin D RdC

Georgia Rapti

The Rockefeller University, Shaham lab, New York, USA.

It takes two to tango with elegance: Glia and pioneer neurons orchestrate C. elegans brain assembly

Invité par Jean-Louis Bessereau

Résumé
Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet, the identities of the pioneer-neurons and of their guidance-substrates and their interactions, are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans possesses radial-glia-like cells key for assembly initiation. Glia guide pioneer and follower axons using distinct signals. Pioneer neurons we identify, with unique growth properties, anatomy, and innervation, cooperate with glia to guide follower axons. We identified a CHIN-1/Chimaerin- KPC-1/Furin double mutant that severely disrupts assembly, unlike previously known mutants. CHIN-1/Chimaerin and KPC-1/Furin cooperate non-canonically in glia and pioneer neurons for guidance-cue trafficking. We exploit this genetic bottleneck to define a guidance-gene network governing assembly, with specific glia and pioneer-neuron contributions. Our studies reveal previously-unknown roles for glia in pioneer-axon guidance, and suggest conserved principles of brain formation.

Annonce de séminaire


Décember 2016

Jeudi 8 Décembre à 14:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Sophie Creuzet

Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Gif-sur-Yvette. France.

Neural crest in forebrain development: from embryology to pathophysiology

Invité par Valérie Castellani

Abstract
In my group, we study the neural crest, a unique cell population that emerges from the primitive neural field and which has a multi-systemic and structural contribution to vertebrate development. Over the last decade, I have been dedicating myself to the cellular and molecular background of the observation I made in 2004, that the cephalic neural crest (CNC), exerts an autonomous and prominent control on forebrain development. This notion has broken the traditional view of how the brain develops. By using exquisite grafting experiments in combination with focal spatially and temporally controlled transgenesis, we have discovered the unexpected and potent “paracrine role that the CNC exerts on forebrain growth and patterning early in development and documented this mechanism at the level of cell interaction, signalling and gene expression. We are now following this exiting line of research, which revisits fundamental concepts in Neurosciences. This notion provides also a conceptual renewal, which is biomedically relevant. The mechanisms identified so far in our model are conserved across tetrapodes, but some social behavioural features are specific to amniotes. Our ongoing project and future directions are to explore the aetiology of neural disorders and behavioural impairments in Humans and in the light of CNC dysfunctions.

Annonce de séminaire


Novembre 2016

Lundi 14 Novembre à 11:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Colin Crist

Department of Human Genetics, McGill University – Québec, Canada.

Translational Control of Muscle Stem Cells

Invité par Rémi Mounier

Abstract
Regeneration of adult tissues depends on somatic stem cells that remain quiescent, yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that accumulating transcripts specifying the myogenic program are not translated in quiescent satellite cells, but are repressed by the action of microRNAs and RNA binding proteins. Furthermore, the reversible nature of microRNA dependent silencing mechanisms may underlie the rapid activation of satellite cells that are poised to enter the myogenic program. We also show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2 at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2 exit quiescence, activate the myogenic program and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Finally, we show that addition of small molecule inhibitors of eIF2α dephosphorylation to muscle stem cell cultures permits their ex vivo expansion and engraftment into a preclinical mouse model of Duchenne muscular dystrophy.

Annonce de séminaire


Jeudi 17 novembre – 11:00 – Amphithéâtre CNRS

Michael A Rudnicki

Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Molecular regulation of muscle stem cell asymmetric division

Invité par Bénédicte Chazaud

Abstract
We discovered that a subset of satellite cells in skeletal muscle are self-renewing stem cells that give rise to myogenic progenitors through asymmetric apical-basal cell divisions. The regulation of asymmetric stem cell division is a key control point that impacts the efficacy of the entire regenerative program. Stem cell polarity is established by the PAR complex, comprised of PAR3/PAR6/aPKC, to regulate self-renewal and expansion. Duchenne Muscular Dystrophy (DMD) is coaused by a lack of dystrophin which is expressed in muscle fibers where it plays a role in ensuring structural integrity. We have made the seminal finding that dystrophin regulates the establishment of PAR-mediated polarity in satellite cells. In the absence of dystrophin, the polarity effector Par1b is dysregulated, leading to the failure of Par3 to become localized to the cortex associated with the basal lamina. Importantly, this results in an abnormal increase in centrosome number, a 10-fold reduction in the numbers of satellite stem cells undergoing asymmetric divisions, and a marked decrease in the generation of myogenin-expressing progenitors. Accordingly, our data suggests that the failure of regenerative myogenesis to keep pace with disease progression in DMD is not due to muscle stem cell exhaustion, but rather is due to a cell-autonomous deficiency in asymmetric division.

Annonce de séminaire


Mardi 22 novembre – 14:00 – Amphithéâtre CNRS

F. Jeffrey Dilworth

Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Epigenetic control of stem cell fate decisions in muscle repair

Invité par Bénédicte Chazaud

Abstract
During muscle regeneration, the conversion of muscle stem cells to terminally differentiated myofibers requires multiple cell fate transitions. Each of these transitions necessitates an alteration in the set of genes being expressed within the cell. In this presentation, our studies on the role of transcription factors and epigenetic enzymes in dictating changes in muscle gene expression will be highlighted. In particular, I will focus on the role for the antagonism between various transcription factors and epigenetic enzymes in controlling the commitment of muscle stem cells towards alternate cell fates.

Annonce de séminaire


Past Seminars

Octobre 2016

Vendredi 21 Octobre à 11:00 – Amphithéâtre CNRS

Fabien Le Grand

Center of Research in Myology, Université Pierre et Marie Curie Paris – France.

Control of muscle stem cell fate by Wnt signaling pathway(s)

Invité par Bénédicte Chazaud

Abstract
Regeneration of the adult skeletal muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). Upon activation following injury or repeated exercise, MuSCs leave quiescence to proliferate and then differentiate to form new muscle fibers while a sub-population exit the cell cycle to self-renew and replenish the stem cell niche. In the course of this process, signals from the microenvironment instruct cycling MuSCs and control myogenesis. We previously demonstrated that numerous Wnt molecules are secreted in the local milieu during regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP signals sent by the regenerating myofibers. To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific ß-catenin Loss-Of-Function or Gain-Of-Function. Strikingly, we observed that induction of either ß-catenin LOF or GOF mutations in MuSCs leads to the impairment of skeletal muscle regeneration following injury. By using a mouse model of conditional APC gene deletion in MuSCs we further demonstrated that the massive activation of canonical Wnt signaling in MuSC following APC loss results in defective cell cycle progression and apoptosis. Mechanistically, we observed that Wnt/ß-catenin signaling orchestrates the cytoplasmic relocalization of the histone 3 lysine 9 methyltransferase Setdb1 during differentiation. We further showed that Setdb1 is required for MuSCs amplification and suppresses myoblast terminal differentiation. Genome-wide analyses showed a Wnt3a-dependant release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation. Taken together, our results demonstrate that both canonical and non-canonical Wnt pathways are necessary for MuSC function. Lastly, I will discuss the potential cross-talks between these two faces of an important signaling.

Annonce de séminaire


Mercredi 5 Octobre à 11:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Stefan Dimitrov

Institut Albert Bonniot, Centre de Recherche UGA – INSERM U1209 / CNRS UMR 5309, Grenoble, France.

Epigenetic strategies : nucleosome remodeling, histone modifications and histone variants.

Invité par Laurent Schaeffer

Abstract
Chromatin impedes the binding of protein factors to the underlying DNA sequences. The cell uses three main “epigenetic tools” to overcome the chromatin barrier, namely, chromatin remodelers, histone variants and histone post-translational modifications. We will give specific examples of how either one of these “epigenetic tools” functions.
Chromatin remodelers are sophisticated nano-machines, which are able to alter histone-DNA interactions and to mobilize nucleosomes. Neither the mechanism of their action nor the conformation of the remodeled nucleosomes are, however, yet well understood. We have studied the mechanism of RSC-induced chromatin remodeling by using high resolution microscopy and state of the art biochemistry techniques. The data illustrates how RSC remodels the nucleosome in vitro and shed light on its in vivo function. The crystal structure of the CENP-A nucleosome was recently solved. Intriguingly, in contrast to the canonical nucleosome (where 147 bp of DNA are wrapped around the histone octamer), only the central 121 bp were visible, suggesting flexible CENP-A nucleosomal ends. Why the CENP-A nucleosome exhibits flexible DNA ends is totally unknown. Our data show that the flexible DNA ends of the CENP-A nucleosome are required for mitotic fidelity.
The Aurora family of oncogenic kinase consists of two major members, Aurora A and Aurora B. Both kinases exhibit very high homology. They show, however, quite distinct localization and function. Histone H3 is specifically phosphorylated, presumably by the oncogenic kinase Aurora B, at serine 10 at the onset of mitosis. Here we will present data on the distinct function of the two Aurora kinases and the mechanism of phosphorylation of histone H3 by Aurora B.

Annonce de séminaire

Vendredi 7 Octobre à 14:00 – Amphithéâtre CNRS

Stéphane Vassilopoulos

Institut de Myologie, UMRS 974 UPMC-Inserm / FRE 3617 CNRS, G. H. Pitié-Salpétrière, Paris – France.

The endocytic machinery in healthy and diseased muscle

Invité par Laurent Schaeffer

Abstract
Costameres represent specialized focal adhesion sites of muscle fibres, located between the plasma membrane and sarcomeres, the contractile units of muscle. When disrupted, they directly contribute to the development of several distinct myopathies.
We have shown that the ubiquitous clathrin heavy chain (CHC), well characterized for its role in intracellular membrane traffic and endocytosis from the plasma membrane (PM), forms large plaques connected to α-actinin and actin filaments. Depletion of CHC leads to defective costamere formation and maintenance both in vitro and in vivo and induces sarcomere disorganization and a loss of contractile force due to the detachment of sarcomeres from the PM. At costameres, CHC is co-expressed with dynamin 2 (DNM2), another key protein of the intracellular membrane trafficking machinery which is mutated in autosomal dominant centronuclear myopathy (CNM). We analyzed the role of DNM2 and several actin binding proteins on clathrin plaque function at costameres in vitro by using either siRNA depletion combined to high resolution electron microscopy or in vivo by intravital microscopy. We also focused on the possible link between costamere and CNM pathophysiology. Using myoblasts from DNM2-mutated patients and using myoblasts and muscles from a knock-in mouse model of DNM2-related myopathy, we analyzed structure of costameres by biochemical and immunocytochemical approaches, as well as their ultrastructure.
Our results demonstrate a crucial role for the endocytic machinery and the cytoskeleton. Their contribution to the formation and maintenance of the contractile apparatus highlight an unconventional role for clathrin flat lattices in skeletal muscle which may be relevant to pathophysiology of several neuromuscular disorders.

Annonce de séminaire

Septembre 2016

Vendredi 30 Septembre à 11:00 – Amphithéâtre CNRS

Sandrine Humbert

GIN – Inserm U1216 – University Grenoble Alpes, Grenoble, France.

Huntingtin regulates cortical development: consequences for Huntington’s disease

Invité par Julien Courchet

Abstract
The bulk of interest in the huntingtin protein has centered on the fact that, when mutated, huntingtin causes Huntington’s disease (HD), a devastating neurodegenerative disorder. The mutation causing HD is an abnormal polyglutamine stretch in huntingtin. Given the adult onset and dysfunction and death of adult neurons characterizing HD, most studies have focused on the toxic effects elicited by mutant huntingtin in post-mitotic neurons. However, the protein is ubiquitous and expressed in the developing embryo where it plays an essential role as revealed by the early embryonic lethality at day 7.5 of the complete knockout of the huntingtin gene in mouse. Anyway, the roles of the wild-type protein during development have been overlooked. I will discuss how huntingtin regulates several steps of mouse embryonic corticogenesis. I will also show the consequences of the presence of an abnormal polyglutamine expansion in huntingtin during cortical neurogenesis and consider the viewing of HD as a developmental disorder.

Annonce de séminaire


July 2016

Mardi 12 juillet a 11:00 – Amphithéâtre CNRS

Jan Tuckermann

Institute of Comparative Molecular Endocrinology Ulm University, Ulm, Germany.

Modes of GR action revised – Novel mechanisms of corticosteroids in inflammation and bone integrity

Invited by Bénédicte Chazaud

Abstract
The Tuckerman Laboratory made major contributions to the molecular mechanisms of corticosteroids in beneficial and side effects of steroid therapy. With the help of conditional and function-selective knockout mice for the glucocorticoid receptor (GR) the lab identified critical cell types and novel mechanisms for anti-inflammatory activities of glucocorticoids in different inflammatory disease models. Furthermore we made the discovery that in a model of lung inflammation the anti-inflammatory action of glucocorticoids is not dependent on the inhibition of pro-inflammatory mediators, but rather requires cooperation with pro-inflammatory signaling pathways (e.g. p38) to induce anti-inflammatory acting genes and alternative polarization of macrophages.

Annonce de séminaire


Juin 2016

Vendredi 24 juin à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Pierre-Jean Corringer

Pasteur Institute, Channel-receptor Unit, CNRS UMR 3571, 25 rue du Docteur Roux, 75015 Paris, France.

Pentameric ligand-gated ion channels functioning at the atomic resolution

Invited by Maëlle Jospin

Abstract
Pentameric channel-receptors, including nicotinic acetylcholine, glycine and GABAA receptors, play a key role in fast excitatory and inhibitory transmission in the nervous system and are the target of numerous therapeutic and addictive drugs. They carry several neurotransmitter binding sites which govern the opening of a transmembrane ion channel. Extensively expressed in animals, they were found in several bacteria, especially the homolog from the cyanobacteria Gloeobacter violaceus (GLIC) which functions as a proton-gated ion channel. The simplified architecture of this archaic homologue, as well as its prokaryotic origin, allowed solving its X-ray structure in several conformations. Those static structures suggest that channel opening occurs through symmetrical quaternary twist and “blooming” motions, together with tertiary deformation. We further engineered multiple fluorescent reporters on the structure, allowing investigating the dynamics of the allosteric reorganizations and showing that activation involves a key pre-active conformation. Finally, the GLIC system was exploited to solve the structure of human receptors through the generation of functional chimeras. Overall, our work gives insights into the mechanism of gating and pharmacological regulation of this important family of neurotransmitter receptors.


Mai 2016

 

Lundi 30 mai à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Yishi Jin

UC San Diego.

Mechanisms regulating synapse maintenance and neural activity

Invited by Jean-Louis Bessereau

Abstract
Synapses are organized subcellular structures that transmit information within the nervous system and to other parts of our body. Our studies use C. elegans have uncovered multiple pathways controlling synapse formation, maintenance and function. Using a genetic model mimicking the physiological state of seizures, our recent work have identified novel regulatory themes affecting presynaptic release machinery. We also discovered that a novel immunoglobulin superfamily (IgSF) transmembrane protein mediates synapse and non-neuronal tissue interaction in synapse maintenance. These findings have implications to our understanding of circuit malfunction under disease conditions.

Annonce de séminaire


Jeudi 26 mai à 11:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Francesco Zorzato

Department of Biomedicine, Basel University

Pathophysiology of ryanodinopathies

Invited by Bruno Allard

Abstract
Type 1 ryanodine receptor (RyR1) is preferentially expressed in skeletal muscle, and mutations in the gene have been associated with malignant hyperthermia, a pharmacogenetic disease, and with several congenital myopathies, including central core disease, multiminicore disease, centronuclear myopathy, congenital fibre type disproportion. Experimental data have indicated that RyR1 is also expressed in some areas of the central nervous system, in some cell types of the immune system and in smooth muscle cells. These results imply that mutations in the gene encoding RyR1 will not only affect skeletal muscles, but other tissues that express this calcium channel as well, thereby broadening the clinical spectrum of disorders due to RyR1 dysfunctions.
The RyR1 is of fundamental importance for the development of muscle force and a decrease in its content may be causally linked to the profound muscle weakness seen in patients with some forms of congenital myopathies linked to recessive RYR1 mutations. The protein composition of the junctional sarcoplasmic reticulum membrane encompassing the excitation-contraction coupling molecular complex (ECCMC) is extremely complicated. Polymorphic variants of the junctional sarcoplasmic reticulum protein JP45 have been shown to segregate in Malignant Hyperthermia Susceptible subjects of Malignant Hyperthermia families in the UK. Thus, some ECCMC accessory proteins may play a role not only in regulating excitation-contraction coupling but also as modifiers of the ryanodinopathies phenotype.

Annonce de séminaire

 


 

Jeudi 19 mai à 11:00 – Amphithéâtre de la délégation du CNRS

Dr. Jean-Marc Goaillard

UNIS – Aix Marseille Université

Biophysical networks underlying electrical phenotype of dopaminergic neurons

Invited by Thomas Boulin

Abstract
Any type of neurons can be easily identified based on its electrophysiological activity, such as its pattern of spontaneous activity, the shape of its action potential, its dendritic integration, etc. How is stability of such electrical phenotype achieved, what are its molecular principles, and what is the degree of robustness of electrical phenotype in the face of different perturbations are questions only very partially answered. We studied these questions on dopaminergic neurons of the substantia nigra pars compacta. Our work involved characterizing the electrical phenotype of these neurons and measuring its post-natal development and its stability at mature stages. We also characterized the specific relationships of electrophysiological parameters underlying the electrical phenotype. In order to determine how complex electrical phenotype is achieved, we then investigated the networks of co-regulation of ion channels at the genetic and at the protein levels. Our results suggest that ion channel gene expression and protein interactions display a modular structure that may be involved in stabilizing phenotype. We also show that electrical phenotype also presents such a modular structure. Our ultimate goal is to provide a systems-level approach to robustness of electrical phenotype.

Annonce de séminaire

 


 

Vendredi 13 mai à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Michele Zoli

 


Avril 2016

Friday Avril 29th at 14:00 – Amphithéâtre de la délégation du CNRS

Dr. Shiva Tyagarajan

Inst. of Pharmacology and Toxicology, University of Zurich.

Interrupting neuronal communication from a GABAergic viewpoint

Invited by Jean-Louis Bessereau

Abstract
In the brain distinct population of inhibitory GABAergic interneurons innervate principal glutamatergic neurons to regulate various aspects of brain function. At the postsynaptic compartment, specific GABAAR subunits are segregated to different neuronal compartments to recieve specific inputs from different interneurons. The correct interpretation of the incoming signal requires functional coupling between the presynaptic neurotransmitter GABA, postsynaptic GABAARs, and downstream signaling by postsynaptic density proteins. The main postsynaptic density protein at inhibitory synapse is gephyrin. In the past decade we have identified diverse signaling cascades that converge on gephyrin scaffold to regulate its scaffolding property, and in turn GABAergic neurotransmission. These studies have shed light into mechanisms that underlie dynamic changes in inhibitory neurotransmission, and how excitation shapes inhibition.

Annonce de séminaire

Janvier 2016

Vendredi 29 janvier à 14:00 – Bâtiment l’Herbier

Pura Muñoz-Cànoves

ICREA Research Professor at Universitat Pompeu Fabra, Barcelona.

Tissue regenerative decline with aging: focus on muscle stem cells

Invited by Bénédicte Chazaud

Abstract
Our group aims to understand the mechanisms regulating stem cell homeostasis and regenerative functions. Research is specially centered on stem cells of skeletal muscle (i.e., satellite cells). Recently, we have focused on two areas: 1) the functional decline of satellite cells with aging; and 2) the physiopathology of muscular dystrophies, with a specific interest in the contribution of inflammation and fibrosis to dystrophy progression. Concerning the first area, work from different laboratories has demonstrated that both environmental and cell- autonomous signals alter satellite cell regenerative potential with aging. I will discuss our latest results showing that satellite cells in their homeostatic quiescent state are equipped with quality control mechanisms to preserve their fitness, and how age-associate alterations in these protective mechanisms lead to stem cell loss of function and regenerative capacity.

Annonce de séminaire

Mai 2019

Lundi 13 Mai- 11:00 – Amphi 4

Marc HAMMARLUND

Yale University, New Haven, USA

How C. elegans neurons sense and respond to injury

Invité par Jean-Louis Bessereau

Abstract
The nervous system has an extraordinary capacity to repair damage by regenerating axons and synaptic connections. I will discuss the molecular and cellular basis of axon regeneration in C. elegans, and describe how regenerated synapses and circuits differ from those generated during development. Finally, I will present new data on a novel ncRNA pathway that controls regeneration.


Mercredi 22 Mai – 11:00 – Amphi 3

Luc BERTRAND

Université catholique de Louvain, Brussels

AMPK in cardiac pathologies, not just a metabolic sensor !

Abstract
The AMP-activated protein kinase (AMPK) has been firstly discovered to be activated under metabolic stress conditions such as myocardial ischemia. Its protective action during an ischemic episode has been demonstrated by several research groups. By targeting metabolism, AMPK helps the heart to survive under such deleterious conditions. However, AMPK action extends beyond metabolism and acute stress conditions. Indeed, it has been more recently shown that AMPK acts as protector of the heart in several chronic diseases such heart failure, diabetic cardiomyopathy and cardiac hypertrophy by acting in cardiomyocytes but also on the other cell types such as fibroblasts. Very recently, our group discovered a connection between AMPK and a particular post-translational modification called O-GlcNAcylation, this interplay acting a major role in the development of cardiac hypertrophy. The lecture will focus on the different protective roles of cardiac AMPK.


Vendredi 24 Mai – 11:00 – Salle Hermann

Michisuke Yuzaki

Keio University School of Medicine, Tokyo

Bridge over troubled synapses — a new synthetic synapse organizer

Invité par Jean-Louis Bessereau

Abstract
Synaptic organizers regulate formation, elimination and maintenance of synaptic connections throughout life. Although excitatory and inhibitory synaptic imbalance underlies certain neuropsychiatric and neurological disorders, no tools are currently available to directly modulate the balance. Recently, a new class of synaptic organizers, termed extracellular scaffolding proteins (ESPs), are reported to acutely and potently modulate specific synapses by directly binding to certain pre- and postsynaptic membrane proteins. Here, to expand the repertoire of ESPs with a variety of pre- and postsynaptic specificities, we developed a new synthetic ESP, Cbln1–neuronal pentraxin 1 (NP1) chimera (CPTX), by exploiting the structure of NP1 and Cbln1. Unlike original Cbln1, CPTX induced excitatory synapses by recruiting AMPA glutamate receptors in vitro. Furthermore, CPTX restored excitatory synapses and synaptic plasticity in vivo, as well as spatial and contextual memories in Alzheimer’s disease model mice. In this talk, I would like to discuss a possible toolkit of ESPs with a variety of pre- and postsynaptic specificities to modify neuronal circuits.


Mars 2019

Lundi 25 Mars à 14:00 – Salle Hermann

Saadi Khochbin

Institute for Advanced Biosciences, La Tronche, France

Les séminaires du Chromatin Club – Metabolism-driven epigenetics

Invité par Armelle Corpet / Patrick Lomonte

Annonce de séminaire


Février 2019

Vendredi 1 Février à 11:00 – Amphi 2bis

Frédéric RELAIX

INSERM – IMRB U955-E10, F-94010 Créteil, France

PAX3 controls the adaptive response of skeletal muscle stem cells to environmental stress

Invité par Rémi Mounier

Abstract
We have identified a molecular link between the Aryl hydrocarbon Receptor (AhR) environmental stress pathway and Pax3/Pax7 developmental genes during craniofacial development. Since Pax3/7 are key regulators of muscle stem cells (muscle satellite cells), we investigated the cellular and molecular impact of chronic 2,3,7,8-Tetrachlorodibenzo-p-Dioxin (TCDD) exposure on skeletal muscle and satellite cells in the adult. We combined in vivo and ex vivo approaches, in order to analyse the impact of chronic exposure to TCDD in several muscles such as tibialis anterior and biceps brachii. While all MuSCs express the transcription factor PAX7, we show that a muscle-specific subset also express PAX3 and exhibit resistance to environmental stress. Upon systemic TCDD treatment, PAX3-negative MuSCs display impaired survival, atypical activation and sporadic differentiation through the xenobiotic Aryl Hydrocarbon Receptor. We further show PAX3-positive MuSCs become sensitized to environmental stress when PAX3 function is impaired and that PAX3-mediated induction of mTORC1-dependent G(alert) is required for protection. Our study therefore identifies a functional heterogeneity of MuSCs in response to environmental stress controlled by PAX3.

Annonce de séminaire


Janvier 2019

Vendredi 25 Janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Nicolas RENIER

ICM – Institut du Cerveau et de la Moelle Epinière Paris – FRANCE

A framework for the study of behaviour and plasticity in the adult brain using light sheet microscopy

Invité par Julien Courchet

Abstract
There has been over the past 6 years a convergence in the fields of optics, biochemistry and computing leading to dramatic improvements in light sheet microscopy, tissue clearing protocols and image analysis algorithms. The convergence of these different fields has the potential to streamline brain studies by accelerating data acquisition speed and reliability over the current whole brain analysis pipelines based on serial sectioning methods. We previously developed the iDISCO+ protocol for immunostaining and imaging intact adult mouse brains. As a companion tool, we also developed and distribute ClearMap, an open source environment to segment objects and map them onto reference atlases optimized for large 3D datasets. We used this pipeline as a discovery tool to find brain regions active in correlation with various behaviors by mapping neuronal activity landscapes derived from Fos expression. Here, I will present recent unpublished projects made possible by our upcoming brain mapping pipeline ClearMap 2, expanding the repertoire of applications derived from intact whole brain preparations. We hope that ongoing developments in light sheet microscopy and image analysis pipelines will facilitate our understanding of individual variations in brain activity, connectivity and structure.

Annonce de séminaire


Novembre 2018

Vendredi 30 November à 11:00 – Salle des Pas Perdus – 1er étage – Faculté de Médecine Lyon Est

Hugues NURY

Institut de Biologie Structurale, Grenoble

Structures and transitions of the serotonin 5-HT3 receptor

Invité par Thomas Boulin

Abstract
The serotonin 5-HT3 receptor is a pentameric ligand-gated ion channel. It belongs to a large family of receptors that transduce signals across the plasma membrane​: upon binding of neurotransmitter molecules to extracellular sites, the receptors undergo complex conformational transitions, which result in transient opening of a pore permeable ​to ions. 5-HT3 receptors are therapeutic targets for emesis and nausea, irritable bowel syndrome and depression. I will present structures of the 5-HT3 receptor obtained by crystallography or cryo-electron microscopy. The structures, obtained in complex with inhibitors or agonists, represent snapshots in different states: inhibited, pre-active, active. Together with molecular dynamics simulations and functional recordings, they reveal the molecular mechanism of the fast neurotransmission mediated by 5HT3 receptors.

Annonce de séminaire


Vendredi 30 Novembre à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est

Emmanuel COMPE

Institut de Génétique et de Biologie Moléculaire et Cellulaire Illkirch, Strasbourg

TFIIH and TFIIE mutations: when transcriptional deficiencies lead to neurological disorders

Invité par Ambra Giglia-Mari

Abstract
Trichothiodystrophy (TTD) is an autosomal recessive disorder mainly related to mutations in the DNA repair/transcription factor TFIIH. In addition to the typical dry and brittle hair, individuals with TTD develop neurological defects, including microcephaly and hypomyelination. Using a TTD transgenic mouse model, we previously observed a spatial and selective deregulation of thyroid hormone target genes in the brain, suggesting that transcriptional failures contribute to TTD phenotypes.
Remarkably, mutations within TFIIE, another general transcription factor, have been recently associated with TTD. Such observation prompted us to accurately dissect the partnerships occurring between TFIIE and TFIIH during transcription. Our work revealed an unexpected dynamic process during which TFIIE act as key factors to recruit and position the kinase module of TFIIH within the preinitiation complex. Strikingly, TTD-related mutations in either TFIIH or TFIIE similarly disrupt this early transcriptional process, which could explain why alterations in different transcription factors can lead to the same clinical syndrome.

Annonce de séminaire


Vendredi 16 Novembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Laurent BARTHOLIN

CRCL, Lyon

The obnoxious faces of TGFbeta in pancreatic cancer

Invité par Rémi Mounier

Abstract
The Transforming growth factor beta (TGFB) is a pleiotropic secreted factor with many roles during embryonic and adult life. In cancer, it behaves either as a tumor suppressor or a tumor promoter. To understand this functional duality, our lab have been using as a model Pancreatic Ductal Adenocarcinoma (PDAC), one of the most aggressive tumor, which is expected to become the second cancer-related cause of death by 2030 (after lung cancer). Our work is focused on the oncogenic properties of TGFB with the final goal to specifically target them by developing innovating therapeutics. During this presentation, I will present our work to understand the TGFB oncogenic effects at the molecular (a “new” oncogenic signaling pathway), cellular (effect on differentiation of pancreatic acinar cells), organ (interaction between PDAC cells and nerves invading the tumor) and whole body levels (interaction with muscle).


Décembre 2018

Vendredi 14 Décembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Fabien LE GRAND

Centre de Recherche en Myologie, Paris

Signaling pathways in muscle tissue regeneration

Invité par Laurent Schaeffer

Abstract
The development and repair of complex metazoan tissues are coordinated by a startlingly small number of evolutionarily conserved signaling pathways. These signals can act in parallel but often function as an integrated hyper-network. Our research aims at understanding the signaling nodes defining this molecular circuitry and the biological significance of pathway cross-talk, using skeletal muscle as a fitting model. Regeneration of the adult muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). We previously demonstrated that numerous WNT molecules are secreted in the local milieu during muscle regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP (1). To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific mutations (2, 3). Mechanistically, we observed that Wnt/ß-catenin signaling orchestrate the cytoplasmic relocalisation of the H3K9 methyltransferase SETDB1 during differentiation (4). We further investigated how Wnt/ß-catenin signaling is connected to Bone morphogenetic protein (BMP) and Transforming growth factor beta (TGF-ß) pathways. Recent work in our lab consisted in dissecting the impact on these pathways on MuSC return to the niche and fusion, respectively. Nevertheless, our understanding of the cells that compose skeletal muscle tissue is limited and molecular definitions of the principal cell types are lacking. This hinders our capacity to decipher signal integration and reciprocity between cells. We thus used a novel combined approach of single-cell RNA-sequencing and mass cytometry and precisely mapped 10 different cell types in adult mouse skeletal muscle, including two previously unidentified populations (5). This cartography yields crucial insights into muscle-resident cell type identities and will be exploited to build a muscle connectome.


Mercredi 19 Décembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Bert Blaauw

Venetian Insitute of Molecular Medicine

The role of mTORC1 signaling in adult skeletal muscle

Invité par Laurent Schaeffer

Abstract
It is well established that mTORC1 signaling is key modulator of skeletal muscle mass and function. Surprisingly, despite the fact that skeletal muscle undergoes major changes in size and contractility in numerous diseases, no genetic loss-of-function model has been generated to determine the effect of inducible deletion of mTORC1 in adult skeletal muscle. Here we generated inducible, muscle-specific Raptor and mTOR k.o. mice. Interestingly, we do not observe a change in muscle size or contractile properties one month after deletion. However, treating these mice with the mTOR-inhibitor rapamycin is sufficient to induce a very rapid and marked myopathy, suggesting that little residual mTOR signaling can maintain muscle homeostasis in adult muscle. Prolonging deletion of Raptor to 7 months, however, leads to a very marked phenotype characterized by muscle dysfunction, regeneration, glycogen accumulation and mitochondrial dysfunction and block in autophagy. Unexpectedly, one of the best markers of reduced mTOR signaling in muscle fibers is the appearance of denervated fibers. Both muscle-specific deletion of mTOR or Raptor, or the use of rapamycin, was sufficient to induce the appearance of numerous NCAM-positive fibers, muscle fibrillation, and neuromuscular junction fragmentation. Taken together, these results link one of the most important anabolic pathways in skeletal muscle fibers to the maintenance of the NMJ.


Octobre 2018

Mardi 9 Octobre à 11:00 – Salle RBC 301

Hélène PUCCIO

Department of Translational Medecine and Neurogenetics, IGBMC, Strasbourg

Advances in Friedreich Ataxia: understanding the function of frataxin and developing therapeutic approaches

Invité par Laurent Schaeffer

Abstract
Friedreich’s ataxia (FA), the most common autosomal recessive ataxia, is characterized by a sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy and increase incidence of diabetes. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Fe-S clusters are ancient and essential cofactors that participate in a number of cellular processes ranging from mitochondrial respiration to DNA metabolism. In eukaryotes, de novo Fe-S biogenesis takes place within mitochondria and relies on proteins that are highly conserved from bacteria to humans. Impaired mitochondrial oxidative phosphorylation, bioenergetics imbalance, deficit of Fe-S cluster enzymes and mitochondrial iron overload occur in individuals with FA. To date, no treatment exists for stopping or slowing FA disease.
Over the past years, we have generated cellular and mouse models that reproduce important progressive pathological and biochemical features of the human disease, including cardiac hypertrophy, mixed cerebellar and sensory ataxia, Fe-S enzyme deficiency, and intramitochondrial iron accumulation. These models have enabled us to demonstrate that Fe-S deficit is a primary event of the disease leading to iron metabolism deregulation through the activation of the iron-regulatory protein, IRP1. These models are excellent models for deciphering the physiopathology of the disease and for testing pre-clinical therapeutic protocols. The latest advances in understanding the pathophysiology will be discussed, with a particular emphasis on new neurological models that are being developed as well as therapeutic approaches.


Mercredi 10 Octobre à 14:00 – Salle des Pas Perdus – 1er étage – Faculté de Médecine Lyon Est

Juliette GODIN

Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg

Pleiotropic activities of the (atypical ?) kinesin KIF21B during cortical development

Invité par Julien Courchet

Abstract
Cortical development progresses through concurrent steps, including neural proliferation, migration and differentiation, that rely on dynamic cell shape remodeling which largely depends on the tight regulation of the microtubules (MT) cytoskeleton. Mutations in tubulin, MT associated proteins or motors have been linked to several neurodevelopmental disorders including malformation of cortical development (MCDs), affecting 2,5% of the world population. Here we identified KIF21B gene as a major locus of human neurodevelopmental disorder. We identified 4 de novo variants in KIF21B gene in patients with intellectual disabilities associated with several brain malformations, including microcephaly, corpus callosum agenesis or facial dimorphism. In support of the pathogenic potential of the discovered alleles, expression of KIF21B variant in mice using in utero electroporation or in zebrafish embryos recapitulated key neurodevelopmental phenotypes, namely migration and microcephaly. In addition, longitudinal neuroanatomical analysis of Kif21b KO model showed strong morphological defects starting prenatally and worsening with time. Finally, we demonstrated that Kif21b regulates migration of projection neurons through the tight control of locomotion and neural shape. Although its motility is dispensable, the regulatory function cytoskeleton dynamics is essential for neuronal migration. Altogether, our data represent an important step to delineate the mechanisms involving KIF21B-mediated MT dynamics and trafficking in the context of brain development.

Annonce de séminaire


Jeudi 11 Octobre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Belinda COWLING

Institut de Génétique et Biologie Moléculaire et Cellulaire, Strasbourg

Myostatin – A novel biomarker for Dnm2 therapy in Myotubular Myopathy mice

Invité par Vincent Gache

Abstract
Centronuclear myopathies (CNM) are non-dystrophic muscle diseases for which no effective therapy is currently available. The most severe form, myotubular myopathy (X-linked CNM), is caused by myotubularin 1 (MTM1) loss-of-function mutations, while the main autosomal dominant form is due to dynamin2 (DNM2) mutations. We have shown that antisense oligonucleotide (ASO) mediated DNM2 knockdown can efficiently correct muscle defects due to loss of MTM1 in mice, providing an attractive therapeutic strategy for this disease. We are now investigating blood-based biomarkers that can be used to monitor disease state and rescue in myotubular myopathy mice. Myostatin is a protein produced and released by myocytes, which acts in an autocrine function to inhibit muscle growth and differentiation. Our results suggest myostatin pathway is ‘turned down’ at the mRNA level in muscle biopsies, leading to low levels of circulating and endogenous muscle myostatin in plasma. We have generated preliminary data suggesting ASO-mediated DNM2 reduction results in an increase in circulating myostatin. With clinical trials for myotubular myopathy currently in progress, identification of novel blood-based biomarkers such as myostatin may allow for monitoring of treatment efficacy in patients.

Annonce de séminaire


Vendredi 12 Octobre à 11:00 – Salle Hermann – 1er étage – Faculté de Médecine Lyon Est

Luisa COCHELLA

Research Institute of Molecular Pathology (IMP), Vienna, Austria

Roles of micro RNAs in animal development: lessons from C.elegans

Invité par Florence Solari

Abstract
One of the main goals of developmental biology is to understand how the different cell types that constitute a multicellular organism are specified during its development. Luisa Cochella is a young PI (awarded for both ERC starting Grant and EMBO Young investigator program) who is currently exploring the different mechanisms of gene expression regulation that control this process. Her lab investigates how the transcriptional history of a cell influences its fate as well as how post- transcriptional mechanisms contribute to the diversification of the genetic programs that control cell fate. Luisa is more specifically interested in both neuronal and muscle differentiation

Annonce de séminaire


Mardi 30 Octobre à 11:00 – Salle Hermann – 1er étage – Faculté de Médecine Lyon Est

Huating WANG

The Chinese University of Hong Kong, Hong Kong, China

Functional investigation of LncRNAs and enhancers in skeletal muscle stem cells

Invité par Bénédicte Chazaud

Abstract
Previously, the majority of the human genome was thought to be « junk » DNA with no functional purpose. Over the past decade, evidence from numerous high-throughput genomic platforms reveals that even though less than 2% of the mammalian genome encodes proteins, a significant fraction can be transcribed into different complex families of non-coding RNAs (ncRNAs). Growing evidence supports that ncRNAs have fundamental roles as regulators of genomic output. Among various types of ncRNAs, microRNAs have dominated the current literature. Other groups, however, such as long ncRNAs (lncRNAs, >200nt), have been largely under explored.
Huating Wang’s lab is currently interested in studying the functional roles of long non-coding RNAs (lncRNAs and enhancers) in regulating gene expression in skeletal muscle stem cells and muscle regeneration.

Annonce de séminaire


Septembre 2018

Mardi 11 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Sonia Garel

Institut de Biologie de l’École Normale Supérieure, Paris

Microglia and prenatal inflammation in early cortical wiring

Invité par Jean-Louis Bessereau

Abstract

Prenatal inflammation and dysfunction of microglia, the brain resident macrophages, have both been associated with the etiology of several neuropsychiatric disorders, including schizophrenia and autism spectrum disorders. Consistently, microglia were shown to regulate neurogenesis, synaptic remodeling and maturation at postnatal stages. However, microglia invade the brain during mid-embryogenesis and could thus exert earlier prenatal and perinatal roles during normal and pathological brain wiring. Here we show that embryonic microglia, which display a transient uneven distribution, regulate the wiring of forebrain circuits. By taking advantage of multiple mouse models, including cell-depletion approaches, we found that perturbing microglia activity affects the development of neocortical inhibitory interneurons, which constitute main actors in neuropsychiatric diseases. In particular, absence, prenatal inflammation or functional perturbation of microglia affects the timely positioning of specific subsets of interneurons as well as their subsequent functional integration in the neocortex. We furthermore found that responses of microglia to environmental signals, including the ones from the microbiome, are sexually dimorphic in males and females. This remarkable finding has major implications for our comprehension of sexual biases in the occurrence of microglia-related diseases, such as the prevalence in males of neurodevelopmental disorders. Our work reveals key roles for immune cells during the normal assembly of cortical circuits and provides novel insights onto how microglia dysfunction or immune risks lead to pathological brain wiring.

Annonce de séminaire


Mercredi 19 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Yasushi Okamura

Graduate School of Medicine, Osaka University Suita

Coupling from electric signal to lipid signal; voltage-sensing phosphoinositide phosphatase

Invité par Vincent Jacquemond

Résumé

Biological membranes have dual roles in cell signaling: insulator for electrical signal by transfer of ion across membrane as well as the place for metabolism for production of lipid mediators such as arachidonic acids or phosphophositides. These two signals interact with each other through changes of ion concentration, mainly intracellular calcium ions, by the concerted activities of ion channels, transporters and GPCRs. There is a rare case where single membrane proteins directly link between electrical signal and lipid-mediated cell signaling. Voltage-sensing phosphatase consists of the ion channel like voltage sensor and PTEN-like phosphoinositide enzyme. In VSP, single voltage sensor regulates the downstream enzyme and the phosphoinositide phosphatase activity is activated by membrane depolarization leading to depletion of mainly PI(4,5)P2. Substrate specificity of VSP is more broad than PTEN; VSP shows both of 3-phosphatase activity and 5-phosphatase activity unlike PTEN which shows the rigid selectivity toward 3-phosphate of the inositol ring of PI(3,4,5)P3 and PI(3,4)P2. However, the key question how transmembrane voltage sensor regulates the cytoplasmic enzyme has remained unanswered, mainly because a method of detecting structural change in the cytoplasmic region has been limited. We have recently applied a method of genetical incorporation of fluorescent unnatural amino acid, Anap, to the cytoplasmic region of Ci-VSP (sea squirt Ciona intestinalis VSP) which was expressed in Xenopus oocyte. This method enables detection of fine structural change reported by fluorescence intensitiy without perturbing the local protein structure. Voltage-dependent fluorescence change of Anap showed two bidirectional changes along the voltage, decrease at low membrane depolarization and increase at higher depolarization, suggesting that the structure of the cytoplasmic region takes multiple conformations. By applying the method to different constructs of Ci-VSP with altered enzyme activity, we obtained evidence that the enzyme takes at least two activated states with distinct magnitude of enzyme activity. Given that voltage sensor of Ci-VSP takes multiple states during activation, it will be intriguing to see in the future how individual enzyme states correlate with states of the voltage sensor.

Annonce de séminaire


Lundi 24 Septembre à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Edgar Gomes

Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal

Mechanisms of nuclear positioning during myofiber formation

Invité par Bénédicte Chazaud

Résumé

Connecting the nucleus to the cytoskeleton is relevant for multiple cellular processes and disruption of these connections result in multiple pathologies. Nuclear positioning within cell cytoplasm requires de connection between nucleus and the cytoskeleton. We are interesting to understand the processes involved in these connections and the role for nuclear positioning in cell function. We study cell migration and skeletal myofiber formation which required the connection between the nucleus and the cytoskeleton and precise nuclear positioning. We use different molecular and cellular approaches in combination with time-lapse imaging analysis to address these questions.

Annonce de séminaire


Jeudi 27 Septembre à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est

Rashmi KOTHARY

Centre for Neuromuscular Disease University of Ottawa

Spinal Muscular Atrophy: a multi-organ disease

Invité par Patrick Lomonte

Abstract

Spinal Muscular Atrophy was characterized in the late 1800s but it was almost 100 years later that the genetic cause was identified as a mutation in the human SMN1 gene. While humans do have two genes that code for SMN, SMN2 only produces 10% protein when compared to SMN1. Early work with mouse models was complicated by the fact that mice only have the one Smn gene which when mutated results in preimplantation lethality. This problem was solved by the development of a mouse model incorporating human SMN2 gene, which was for years the only viable mouse model. Now, there are over a hundred mouse models available that have served to inform our understanding of pathogenesis in SMA.
Classically, SMA is described as a motor neuron disease; however, SMN is expressed ubiquitously throughout the body. In fact, SMA is emerging to be a multi-organ disease with SMN depletion having impacts on many tissues in the body. Subcutaneous administration of available treatments may address these affected organs better than intrathecal administration. Also, systemic gene therapies that are currently under development may help repair function in these other organs.
Dr. Kothary will present on the work in his laboratory on the multi-organ nature of SMA. Defects in various tissues will be discussed.

Annonce de séminaire


Juin 2018

Vendredi 29 Juin à 11:00 – Amphi 3 – Faculté de Médecine Lyon Est – 3ème étage

Laure STROCHLIC

Institut de Myologie – Centre de Recherche en Myologie, Sorbonne Université, INSERM AIM UMRS974, Paris

Regulation of neuromuscular connectivity by Wnt signaling from signaling molecules to therapeutic strategies

Invité par Rémi Mounier

Résumé

The development and maintenance of the neuromuscular connectivity relies on a temporally fine-tuned balance of distinct bi-directional communication between motor neurons and their muscle targets. Disruption of this communication leads to structural and functional defects that affect the motor function and causes severe neuromuscular pathologies. Wnt signaling participates in various developmental mechanisms such as migration, axonal guidance or synaptogenesis. But how the Wnt signaling network could regulate neuromuscular connectivity and how it could affect motor function is unknown. In this presentation, I will provide data using Wnts gain or loss of function studies in cell culture or in mice showing that distinct branches of Wnt signaling, acting in part via the muscle-specific kinase MuSK regulate several key aspects of the formation and maintenance of the neuromuscular synapse including pre and postsynaptic differentiation/stabilization, retrograde control of motor axon outgrowth and synapse-specific gene expression. I will also present evidence showing that the pharmacological modulation of Wnt signaling in a pathological context could be used as a therapeutic strategy to counteract neuromuscular junction (NMJ)- associated disorders. Overall, our results provide novel insights into the mechanisms by which synaptic diffusible cues act to prevent NMJ dysfunction, muscle weakness and disease.

Dans cette présentation, je fournirai des données, utilisant des approches expérimentales in vitro et in vivo chez la souris, qui montrent le rôle émergent de la signalisation Wnt dans la régulation de la connectivité neuromusculaire dans un contexte physiologique et pathologique.

Annonce de séminaire


Mai 2018

Vendredi 4 Mai à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Helge AMTHOR

Université de Versailles – Paris Saclay Laboratoire U1179 UVSQ – INSERM

BMP signaling controls limb muscle development and maintenance

Invité par Laurent Schaeffer

Résumé
Bone morphogenetic proteins (BMPs) regulate the activity of skeletal muscle precursors as well as the trophic state of differentiated muscle. Here, the role of BMP signaling was explored at different stages of limb muscle development by overexpressing an inhibitory Smad protein (Smad6) to abrogate the BMP signaling cascade at cell autonomous level. Overexpression of Smad6 in limb muscle precursors during development (crossing Rosa26-Lox-Stop-Lox-Smad6-IRES-GFP mice, termed RS6, with Lbx1Cre/+ transgenic mice) disturbed limb muscle myogenesis: early myogenic markers Pax3 and MyoD were strongly downregulated, fetal limb muscles were smaller, consisted of fewer myofibers and displayed a disturbed muscle patterning. Overexpression of Smad6 in postnatal muscle precursors (using RS6: Pax7CreERT2/+ mice) caused decreased cell proliferation resulting in smaller myofibers containing less myonuclei and in decreased generation of satellite cells. Overexpression of Smad6 in differentiated muscle resulted in a different phenotype (using RS6:HSA-Cre mice): limb muscles were only modestly smaller, however, consisted of fewer but larger myofibers with increased myonuclear number. Overexpression of the BMP antagonist Noggin in adult muscle (loss-of-function) resulted in muscle fiber atrophy, whereas overexpression of the BMP receptor Alk3 (gain-of-function) caused muscle fiber hypertrophy. These latter effects were likely muscle precursor independent, as overexpression of Smad6 in differentiated fibers (using RS6:Pax7CreERT2/+ mice) had no effect on satellite cell number and muscle size in the adult. In conclusion, the role of BMP signaling in skeletal muscle is stage and context specific.

Annonce de séminaire


Mercredi 16 Mai à 11:00 – Salle des Pas Perdus, 1er étage

Vanina ROMANELLO

Venetian Institute of Molecular Medicine, Padova

The role of the myokine FGF21 in skeletal muscle homeostasis

Invité par Rémi Mounier

Résumé
Skeletal muscle is a major site of metabolic activity and the most abundant tissue in the human body accounting for almost 40% of the total body mass. It is a plastic tissue that adapts to changes in exercise, nutrition and hormones, which also induces the release of myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine and endocrine effects, explaining how muscles regulate metabolic homeostasis in other tissues. These systemic effects help to explain why physical activity, and thereby muscle recruitment, elicits several beneficial effects in many different diseases. Indeed, exercise preserves and ameliorates mitochondrial function and muscle metabolism, thereby affecting the release of myokines and metabolites that systemically counteract organ deterioration. We have recently proposed an interplay between the myokine Fgf21 and the mitochondrial quality control pathways that greatly contributes to a pro-senescence metabolic shift. However, even though the myokine field is exponentially increasing, little is known about their role in muscle homeostasis.

Annonce de séminaire


Jeudi 31 Mai à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Robert J. Johnston

Johns Hopkins University, Baltimore, USA

Stochastic gene expression and nuclear architecture in fly eyes and human retinal organoids

Invité par Thomas Boulin

Résumé
A central challenge in developmental neurobiology is to understand how the myriad types of neurons in the human nervous system are generated. Stochastic gene expression mechanisms are crucial to differentiate neuronal subtypes and expand function. During stochastic fate specification, individual neurons randomly choose between different fates, resulting in unique patterns but consistent proportions of cell types among genetically identical organisms. My lab studies the stochastic mechanisms that specify the color-detecting photoreceptors in the fly and human retina. Fruit flies have a well-characterized retina and an abundance of genetic tools that enable molecular analyses of gene regulatory mechanisms. To overcome the challenges associated with human studies, we have developed a human retinal organoid system that recapitulates retinal development and photoreceptor specification. With these systems, we are interrogating how DNA elements, trans factors, and chromatin architecture control random on/off gene expression. Our molecular approaches are complemented by quantitative genetics to determine how natural variation in the genome impacts gene expression and photoreceptor specification. Finally, we conduct behavioral and functional assays to measure differences in color perception when photoreceptor fates are altered. By studying highly divergent organisms from multiple angles, we aim to define the unifying principles underlying stochastic fate specification during nervous system development.

Annonce de séminaire


Avril 2018

Vendredi 6 Avril à 11:00 – Salle des Pas Perdus, 1er étage

Athanassia SOTIROPOULOS

Institut Cochin, Paris

Role of Srf transcription factor and F-actin scaffold in muscle stem cell fusion

Invité par Rémi Mounier

Résumé
Our team is interested on how signaling pathways control of adult skeletal muscle plasticity. In the past years, we focused our attention on Srf transcription factor which is one of the three master genes that controls myogenesis in Caenorhabditis elegans, together with MyoD and HAND. We investigated the role of Srf in two cellular compartments of mouse skeletal muscle (myofibers and adult muscle stem cells) upon different perturbation of muscle homeostasis (hypertrophy, atrophy, regeneration). In the present seminar, I will summarize our findings concerning the role of Srf in myofibers to control muscle mass and I will present recent data identifying Srf as a master regulator of muscle stem cell fusion and demonstrating the implication of F-actin architecture in this process.

Seminar announcement


Mars 2018

Vendredi 16 mars à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Cécile MARTINAT

INSERM/UEVE UMR861, I-STEM, AFM

Human pluripotent stem cells for the study and treatment of neuromuscular diseases : myth or reality ?

Résumé
Neuromuscular diseases correspond to a vast group of diseases that perturbs the function of the skeletal muscles by affecting motoneurons, muscles and/or NMJs. To date, no efficient curative treatments have been identified for NMD. Progresses towards identification of new treatment have been hampered by the incomprehension of disease pathogenesis, particularly in early phases, as well as the availability of relevant screening tools. Disease-specific human pluripotent stem cells, from embryonic origin or derived from reprogramming somatic cells, offer the unique opportunity to have access to a large spectrum of disease-specific cell models. Due to their ability of self-renewal and differentiation into various tissues affected in each pathological condition, the development of these human disease-specific pluripotent stem cells provide new insights in pathological mechanisms implicated in human diseases for which, accessing homogenous affected tissues is often challenging. Validating this concept, we previously demonstrated that human pluripotent stem cells and derivatives which, express the causal mutation implicated in the Myotonic Dystrophy type 1 (DM1), offer pertinent disease-cell models, applicable for a wide systemic analysis ranging from mechanistic studies to therapeutic screening. Thus, we identified, through a genome-wide analysis, two early developmental molecular involved both in myogenesis as well as in neurite formation and establishment of neuromuscular connections. These neuropathological mechanisms may bear clinical significance as related to the functional alteration of neuromuscular connections associated with DM1. In parallel to these functional pathological studies, we also demonstrated the pertinence of this new disease-specific cell model to identify new therapeutic strategies. Thus, our results identified the possibility to repurposing metformin, the most commonly prescribed drug for type 2 diabetes, for DM1 leading to a phase 2 clinical trial that is actually ongoing.
We are now extending our approach to another incurable neuromuscular disease, spinal muscular atrophy (SMA). This disease, considered as the leading genetic cause of infant death, is due to mutations or deletions in the « Survival of Motor Neuron » gene, SMN1, which results in low levels of the expressed SMN protein. Despite this ubiquitous SMN expression, the pathology is characterized by degeneration of spinal Motor neurons whereas other neuronal types are relatively preserved suggesting that spinal motor neurons specific features control this differential sensitivity. Based on our recent development allowing the efficient and robust conversion of human pluripotent stem cells into affected spinal motor neurons and non- affected cranial motor neurons, our objective is to deepen the mechanisms involved in the specific degeneration of spinal motor neurons in SMA as well as the mis communication of these neurons with their muscular target.

Annonce de séminaire


Lundi 19 Mars à 10:00 – Amphi 4 – 4e étage

Christoph Hoefer, M. Sc.

Senior Business Development Manager ; Life Sciences Solutions, Cell Biology, ThermoFisherScientific

Séminaire Technique : Travailler avec des iPSC (induced Pluripotente Stem Cell)

Résumé
Les cellules souches pluripotentes humaines (iPSC) sont des outils puissants pour la recherche en biologie du développement, la médecine régénérative et l’étude des pathologies humaines. Les données obtenues à partir de modèles physiologiques in vitro amélioreront grandement notre compréhension des processus biologiques. Dans cette présentation, j’aborderai les principaux défis rencontrés dans la mise en place des cellules souches pluripotentes au sein d’un laboratoire et les améliorations récentes apportées à la construction de modèles pour les maladies humaines, telles que la reprogrammation, l’expansion, la transfection, la préservation et la différenciation efficace de iPSC, ainsi que les options de modifications génomiques.

Annonce de séminaire


Vendredi 2 Mars à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Nicolas PLACE

Institute of sport Sciences, University of Lausanne

Skeletal muscle adaptations to exercise : a translational approach

Invité par Julien Gondin

Résumé
The amount of force skeletal muscles can produce depends on their contractile history. For instance, repeated contractions generally lead to reduced muscle force generating capacity, namely muscle fatigue. Although muscle fatigue has been the focus of many works in the last 100 years, the underlying mechanisms remain elusive. In this presentation, special emphasis will be given to the role of Ca2+ handling as a key regulator of (i) muscle weakness and (ii) beneficial adaptations observed after high intensity interval training. In particular, the potential role of the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor type 1, will be discussed.

Annonce de séminaire


Lundi 5 Mars à 14:00 – Salle des Conférences – Médiathèque Paul Zech

Julien OCHALA

Faculty of Life Sciences & Medicine, King’s College, London

Actinopathies : From Mutations to Treatment

Invité par Laurent SCHAEFFER

Résumé
Actinopathies are genetically and clinically heterogeneous disorders mainly characterized by generalized muscle weakness. The understanding of this group of disorders has advanced in recent years through the identification of the causative mutations in the gene encoding one of the major proteins of the basic contractile unit of skeletal muscle, i.e., actin. In the present seminar, I will present (i) how these gene mutations lead to generalized muscle weakness and (ii) the advances regarding potential therapies.

Annonce de séminaire


Février 2018

Vendredi 9 Février à 14:00 – Salle des Conférences – Médiathèque Paul Zech

Norbert WEISS

Institute of Organic Chemistry and Biochemistry, Prague

Trafficking of T-type calcium channels in health and disease

Invité par Vincent JACQUEMOND

Résumé
T-type calcium channels are key contributors to neuronal physiology where they shape electrical activity of nerve cells and contribute to the release of neurotransmitters. Alteration of T-type channel expression has been causally linked to a number of pathological conditions including neuropathic pain and absence seizure activity. Although a number of signaling pathways regulating the activity of T-type calcium channels have been reported, the molecular machinery and signaling molecules controlling the trafficking and expression of the channel protein at the plasma membrane remain largely unknown. I will present some of the basic mechanisms recently identified controlling the physiological trafficking of T-type channels, and illustrate how metabolic defects or congenital mutations can disturb this trafficking machinery and eventually leading to disease conditions.

Annonce de séminaire


Janvier 2018

Mardi 30 janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Isabelle JANOUEIX

Institut Curie – Inserm U8330, Paris

Understanding neuroblastoma biology through the analysis of its genetic and epigenetic landscapes

Invité par Valérie Castellani

Résumé
Neuroblastoma is an embryonal neoplasm arising from the peripheral nervous system that accounts for 15% of cancer deaths in childhood. It is an enigmatic tumor presenting with a great genetic and clinical heterogeneity, both in terms of presentation and outcome.
The characterization of the genetic alterations observed in neuroblastoma led to the identification of major players of neuroblastoma oncogenesis that has considerably improved our understanding of the biology of this pediatric cancer. More recently, the analysis of the super-enhancer landscape allowed to decipher the core regulatory circuitries controlling the gene expression program of neuroblastoma. Distinct transcription factor networks predicate different tumor identities, corresponding to sympathetic noradrenergic or mesenchymal/neural-crest cell like identities. Cells of mesenchymal identity are more resistant to chemotherapeutic agents. Moreover, some neuroblastoma cells exhibit plasticity and are able to shift between the NCC-like and noradrenergic identities.
The understanding of cell identity, heterogeneity and plasticity in neuroblastoma has strong implications with respect to the development of new therapeutic strategies to eradicate tumor cells in neuroblastoma patients.

Annonce de séminaire


Mercredi 10 janvier à 11:00 – Salle des Conférences – Médiathèque Paul Zech

Justin FALLON

Brown University, Providence, RI

MuSK as a BMP co-receptor

Invité par Laurent Schaeffer


Décembre 2017

Vendredi 1er Décembre à 11:00 – Amphithéâtre CNRS

Chantal Thibert

Institute for Advanced Biosciences, Université Grenoble Alpes

The tumor suppressor LKB1 controls cell fate through pyruvate-alanine transamination

Invité par Julien Courchet

Résumé
The tumor suppressor LKB1 (also named STK11) codes for a serine/threonine kinase. LKB1 acts as a key regulator of cell polarity as well as energy metabolism partly through the activation of the AMP-activated protein kinase (AMPK), a sensor that adapts energy supply to the nutrient demands of cells facing situations of metabolic stress.
To determine if Lkb1 exerts a coordinated regulation of energy metabolism and cell polarity, we deleted the Lkb1 gene in polarized cells and explored the metabolic consequences. In particular, we generated spatio-temporal ablation of Lkb1 in a subpopulation of mouse embryonic multipotent neural crest cells (NCC) that originate from the neural tube and give rise to a broad range of derivatives including most of the face, the melanocytes, the peripheral nerves and the enteric nervous system (ENS). Mutant mice exhibited craniofacial malformations, hypopigmentation, intestinal pseudo-obstruction and hindlimb paralysis. Further phenotypic characterization revealed that LKB1 is required for the differentiation and maintenance of two NCC-derivatives, Schwann cells and the ENS. Using a model of neural crest stem cell line, we demonstrated that Lkb1 is key for neural crest-derived glial commitment. Mechanistically, Lkb1 loss led to an increase of alanine and glutamate levels and inhibition of pyruvate-alanine transamination rescued glial differentiation of Lkb1-null NCC, in a mTOR dependent manner. Furthermore, AICAR, an analogue of AMP, rescued glial differentiation of Lkb1-deficient NCC and corrected the Schwann cells and ENS phenotypes of Lkb1 mutant mice.
Altogether, these findings highlight the central role of Lkb1 during neural crest cell lineage and uncovered a link between Lkb1-mediated pyruvate-alanine cycling and glial commitment. These results provide also new insights for the understanding of metabolic events that contribute to the formation of LKB1-deficient malignancies.

Annonce de séminaire


Novembre 2017

Vendredi 10 Novembre à 11:00 – Amphithéâtre CNRS

Michalis Averof

Institut de Génomique Fonctionnelle de Lyon (IGFL).

Live imaging of regenerating legs: cell dynamics and progenitors

Invité par Rémi Mounier

Résumé
Regeneration is a complex and dynamic process, mobilising diverse cell types and remodelling tissues over a long time period. Compared with embryonic development, it is less genetically tractable and less accessible for direct observation. I will describe our recent efforts to establish a small crustacean, Parhyale hawaiensis, as an experimental model for studying regeneration. Using transgenic markers and live imaging we are starting to describe the cell behaviours and progenitors that underpin limb regeneration. We find that crustacean limb regeneration relies lineage-committed progenitor cells: muscles derive from satellite-like stem cells, whereas epidermis regenerates from existing epidermal cells.

Annonce de séminaire


Octobre 2017

Jeudi 12 Octobre à 11:00 – Salle Fontanes, Darwin D

Damaris Lorenzo

University of North Carolina at Chapel Hill

Ankyrin-B and beta-II spectrin in axonal transport and brain connectivity

Invité par Thomas Boulin

Résumé
The formation, targeting, and maintenance of axon and dendrites are critical for proper brain development and synaptic function. Deficits in synapse establishment and maturation can lead to neurodevelopmental, neurodegenerative, and psychiatric disorders. The neuronal cytoskeleton regulates the architecture and dynamics of synaptic processes by providing structural support and the tracks for motor protein-based synaptic transport. The latter is particularly important for the establishment of long axonal projections, which requires coordinated long-range organelle transport. The membrane associated adaptor ankyrin-B (AnkB) promotes fast axonal transport and elongation by coupling dynactin to multiple organelles through binding to phosphatidylinositol 3-phosphate lipids in these cargos. Additionally, AnkB directly binds βII-spectrin, which, in turn, controls the formation of a ring-shaped membrane periodic skeleton (MPS) in axons and mature dendrites. Interestingly, βII-spectrin also associates with molecular motors. I will show that AnkB and βII-spectrin are key elements in independent and overlapping pathways responsible for the transport of synaptic cargo and other organelles, and are essential for establishing proper brain structural and functional connectivity.

Annonce de séminaire


Mai 2017

Vendredi 12 mai à 11:00 – Amphithéâtre CNRS

Andre Brown

MRC London Institute of Medical Sciences – Imperial College, London

Syntax in C. elegans locomotion

Invité par Thomas Boulin

Résumé
Behaviour is a striking phenotype and often one of the first things we notice about an animal. Broadly speaking, we are interested in understanding how genes affect behaviour, but despite rapid advances in technology for sequencing and engineering genomes, it is still a challenge to associate particular genes with heritable behavioural differences because behaviour is time consuming to measure and difficult to quantify. We are using automated imaging to record the behaviour of freely moving nematode worms and developing new analysis methods to extract relevant features. I will discuss unsupervised methods to quantify behavioural repertoires, and how making connections to language processing and data compression can give insight into the structure of behaviour. Finally I will show how these new representations can advance the study of behavioural genetics and phenotypic drug screening.

Annonce de séminaire


Mercredi 17 mai à 14:00 – Salle Guillermond – Bât. L’Herbier

Hélène CASTEL

Normandie Rouen University / Inserm 1239 – Équipe Astrocyte and Vascular Niche

Cancer and Cancer treatments on cognition: A major translational impact of the preclinical research

Invité par Virginie DESESTRET

Résumé
Co-head Cancer and Neurosciences axis Northwest canceropole, Cancer and cognition platform; ICCTF member (editing of preclinical research guidelines).
The emergence of a new field in oncology addressing cognitive deficits in cancer patients is justified by the existence of deficits in memory, concentration and attention, as well as executive functions before, during and after treatments, symptoms often referring to the “chemofog” or “cancerfog”. Our work mainly involves research and clinical groups of Normandie developing programs in patients and animal models, to improve our understanding of the impact of cancer and its treatments on cognitive functions. Two main examples of these translational studies we participated on can be exposed:
The first Cog-Age clinical study (Pr F. Joly, Baclesse Caen) showed that cognitive decline can be detected 6 months after chemotherapy in breast cancer elderly patients. In a mirror study, chemotherapy administration in young and elderly mice resulted in a change in behavioral flexibility and alteration of neuron precursor proliferation in the hippocampal dentate gyrus. We were thus able to conclude that age-related cognitive decline is accentuated by chemotherapy, providing basis for questioning the place of adjuvant chemotherapy in this elderly patient population. The second clinical study COG-ANGIO (Pr Joly) demonstrated that antiangiogenics exert a direct negative impact on cognitive functions and fatigue in kidney cancer patients. In mice, the anti-angiogenic mTOR inhibitor everolimus did not alter cognitive functions but led to weight loss and modification of cell metabolism in brain regions involved in sleep/wake cycle or food intake, likely connected to fatigue. On the other hand, immunoneutralizing VEGF (Genentech-Roche, MTA) impaired spatial learning performance and neuronal activity of CA3 hippocampus neurons. These data suggest that a careful and systematic evaluation of targeted cancer therapies on cognitive functions in preclinical models may constitute a strategy of prevention by selection of treatments exhibiting minimum brain co-morbidities.
Together, this translational program is developed within the National Cancer and Cognition Platform (CNO/Ligue Nationale contre le cancer), with the aim to collaborate in a structured way with French oncology groups, research teams as well as pharmaceutical industry, by providing preclinical models and guidance on standard operating procedures for ancillary or future studies in identified population at risk.

Annonce de séminaire


Mars 2017

Vendredi 31 Mars à 11:00 – Salle FONTANNES – Bât. Darwin D RdC

Kei Sakamoto

Institut des Nestlé Institute of Health Sciences SA, Lausanne.

Key signaling players in the control of hepatic gluconeogenesis — AMPK or other AMPK-related/AMP-regulated enzymes ?

Invité par Rémi Mounier

Résumé
Hepatic glucose production is a key physiologic process that ensures energy balance for glucose-dependent organs/cells such as brain. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type 2 diabetes. LKB1, originally identified as a tumor suppressor protein, is currently thought as a critical regulator of cellular metabolism and growth by controlling the activity of AMP-activated protein kinase (AMPK) and also 12 other kinases that are closely related to AMPK. Among those AMPK-related kinases, we have recently identified that Salt-Inducible Kinase (SIK) plays an important role as a gluconeogenic gatekeeper in the liver.
Metformin exerts its major effect via inhibition of hepatic glucose production. This is thought to be mediated through decreased hepatic energy charge (i.e. increasing AMP/ATP ratio) via inhibition of mitochondrial respiration. The long-standing belief that 5’-adenosine monophosphate (AMP)-activated protein kinase (AMPK) mediates the anti-hyperglycaemic action of metformin has recently been challenged in experiments using mice lacking hepatic AMPK. I will discuss our recent data demonstrating AMP-mediated allosteric inhibition of an enzyme involved in gluconeogenesis plays a key role in acute glucose-lowering effect of metformin.

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Janvier 2017

Jeudi 12 Janvier à 14:00 – Amphithéâtre CNRS

Alexandre Pattyn

Institut des Neurosciences de Montpellier, INSERM U1051. France.

Heterogeneous precursor populations underlie developmental plasticity of the dorsal root ganglia

Invité par Valérie Castellani

Résumé
Although a variety of primary sensory neurons are implicated in the detection and transmission of different sensory modalities, how they arise during development remains poorly understood. The process of neuronal specification is the acquisition of definitive phenotypic characteristics for a given subclass of neurons during embryonic development. This acquisition can be divided into several interdependent and sequential phases, from the time point when progenitor cells exit the cell cycle toward the newly formed and perfectly differentiated neuron. Using mouse genetics, Alexandre demonstrated that transcriptions factors of Maf and Zeb families control the specification and differentiation of specific sensory neuron sub-types. His work contributed to uncover the complex developmental sequence ensuring the formation of the peripheral sensory system and to highlight the progenitor diversity that underlies the developmental plasticity of sensory neuron generation.

Annonce de séminaire


Jeudi 19 Janvier à 11:00 – Salle FONTANNES – Bât. Darwin D RdC

Georgia Rapti

The Rockefeller University, Shaham lab, New York, USA.

It takes two to tango with elegance: Glia and pioneer neurons orchestrate C. elegans brain assembly

Invité par Jean-Louis Bessereau

Résumé
Brain assembly is hypothesized to begin when pioneer axons extend over non-neuronal cells, forming tracts guiding follower axons. Yet, the identities of the pioneer-neurons and of their guidance-substrates and their interactions, are not well understood. Here, using time-lapse embryonic imaging, genetics, protein-interaction, and functional studies, we uncover the early events of C. elegans brain assembly. We demonstrate that C. elegans possesses radial-glia-like cells key for assembly initiation. Glia guide pioneer and follower axons using distinct signals. Pioneer neurons we identify, with unique growth properties, anatomy, and innervation, cooperate with glia to guide follower axons. We identified a CHIN-1/Chimaerin- KPC-1/Furin double mutant that severely disrupts assembly, unlike previously known mutants. CHIN-1/Chimaerin and KPC-1/Furin cooperate non-canonically in glia and pioneer neurons for guidance-cue trafficking. We exploit this genetic bottleneck to define a guidance-gene network governing assembly, with specific glia and pioneer-neuron contributions. Our studies reveal previously-unknown roles for glia in pioneer-axon guidance, and suggest conserved principles of brain formation.

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Décember 2016

Jeudi 8 Décembre à 14:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Sophie Creuzet

Institut des Neurosciences Paris-Saclay, CNRS UMR 9197, Gif-sur-Yvette. France.

Neural crest in forebrain development: from embryology to pathophysiology

Invité par Valérie Castellani

Abstract
In my group, we study the neural crest, a unique cell population that emerges from the primitive neural field and which has a multi-systemic and structural contribution to vertebrate development. Over the last decade, I have been dedicating myself to the cellular and molecular background of the observation I made in 2004, that the cephalic neural crest (CNC), exerts an autonomous and prominent control on forebrain development. This notion has broken the traditional view of how the brain develops. By using exquisite grafting experiments in combination with focal spatially and temporally controlled transgenesis, we have discovered the unexpected and potent “paracrine role that the CNC exerts on forebrain growth and patterning early in development and documented this mechanism at the level of cell interaction, signalling and gene expression. We are now following this exiting line of research, which revisits fundamental concepts in Neurosciences. This notion provides also a conceptual renewal, which is biomedically relevant. The mechanisms identified so far in our model are conserved across tetrapodes, but some social behavioural features are specific to amniotes. Our ongoing project and future directions are to explore the aetiology of neural disorders and behavioural impairments in Humans and in the light of CNC dysfunctions.

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Novembre 2016

Lundi 14 Novembre à 11:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Colin Crist

Department of Human Genetics, McGill University – Québec, Canada.

Translational Control of Muscle Stem Cells

Invité par Rémi Mounier

Abstract
Regeneration of adult tissues depends on somatic stem cells that remain quiescent, yet are primed to enter a differentiation program. The molecular pathways that prevent activation of these cells are not well understood. Using mouse skeletal muscle stem cells as a model, we show that accumulating transcripts specifying the myogenic program are not translated in quiescent satellite cells, but are repressed by the action of microRNAs and RNA binding proteins. Furthermore, the reversible nature of microRNA dependent silencing mechanisms may underlie the rapid activation of satellite cells that are poised to enter the myogenic program. We also show that a general repression of translation, mediated by the phosphorylation of translation initiation factor eIF2 at serine 51 (P-eIF2α), is required to maintain the quiescent state. Skeletal muscle stem cells unable to phosphorylate eIF2 exit quiescence, activate the myogenic program and differentiate, but do not self-renew. P-eIF2α ensures in part the robust translational silencing of accumulating mRNAs that is needed to prevent the activation of muscle stem cells. Additionally, P-eIF2α dependent translation of mRNAs regulated by upstream open reading frames (uORFs) contributes to the molecular signature of stemness. Finally, we show that addition of small molecule inhibitors of eIF2α dephosphorylation to muscle stem cell cultures permits their ex vivo expansion and engraftment into a preclinical mouse model of Duchenne muscular dystrophy.

Annonce de séminaire


Jeudi 17 novembre – 11:00 – Amphithéâtre CNRS

Michael A Rudnicki

Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Molecular regulation of muscle stem cell asymmetric division

Invité par Bénédicte Chazaud

Abstract
We discovered that a subset of satellite cells in skeletal muscle are self-renewing stem cells that give rise to myogenic progenitors through asymmetric apical-basal cell divisions. The regulation of asymmetric stem cell division is a key control point that impacts the efficacy of the entire regenerative program. Stem cell polarity is established by the PAR complex, comprised of PAR3/PAR6/aPKC, to regulate self-renewal and expansion. Duchenne Muscular Dystrophy (DMD) is coaused by a lack of dystrophin which is expressed in muscle fibers where it plays a role in ensuring structural integrity. We have made the seminal finding that dystrophin regulates the establishment of PAR-mediated polarity in satellite cells. In the absence of dystrophin, the polarity effector Par1b is dysregulated, leading to the failure of Par3 to become localized to the cortex associated with the basal lamina. Importantly, this results in an abnormal increase in centrosome number, a 10-fold reduction in the numbers of satellite stem cells undergoing asymmetric divisions, and a marked decrease in the generation of myogenin-expressing progenitors. Accordingly, our data suggests that the failure of regenerative myogenesis to keep pace with disease progression in DMD is not due to muscle stem cell exhaustion, but rather is due to a cell-autonomous deficiency in asymmetric division.

Annonce de séminaire


Mardi 22 novembre – 14:00 – Amphithéâtre CNRS

F. Jeffrey Dilworth

Center of Ottawa Hospital Research Institute, Ottawa, Ontario, Canada

Epigenetic control of stem cell fate decisions in muscle repair

Invité par Bénédicte Chazaud

Abstract
During muscle regeneration, the conversion of muscle stem cells to terminally differentiated myofibers requires multiple cell fate transitions. Each of these transitions necessitates an alteration in the set of genes being expressed within the cell. In this presentation, our studies on the role of transcription factors and epigenetic enzymes in dictating changes in muscle gene expression will be highlighted. In particular, I will focus on the role for the antagonism between various transcription factors and epigenetic enzymes in controlling the commitment of muscle stem cells towards alternate cell fates.

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Past Seminars

Octobre 2016

Vendredi 21 Octobre à 11:00 – Amphithéâtre CNRS

Fabien Le Grand

Center of Research in Myology, Université Pierre et Marie Curie Paris – France.

Control of muscle stem cell fate by Wnt signaling pathway(s)

Invité par Bénédicte Chazaud

Abstract
Regeneration of the adult skeletal muscle tissue relies on a pool of quiescent muscle stem cells located in a niche around the myofibers: the satellite cells (MuSCs). Upon activation following injury or repeated exercise, MuSCs leave quiescence to proliferate and then differentiate to form new muscle fibers while a sub-population exit the cell cycle to self-renew and replenish the stem cell niche. In the course of this process, signals from the microenvironment instruct cycling MuSCs and control myogenesis. We previously demonstrated that numerous Wnt molecules are secreted in the local milieu during regeneration and showed that MuSC self-renewal is in part controlled by non-canonical Wnt7a/PCP signals sent by the regenerating myofibers. To elucidate the roles of the canonical Wnt/ß-catenin pathway in MuSCs, we generated mice with inducible MuSC-specific ß-catenin Loss-Of-Function or Gain-Of-Function. Strikingly, we observed that induction of either ß-catenin LOF or GOF mutations in MuSCs leads to the impairment of skeletal muscle regeneration following injury. By using a mouse model of conditional APC gene deletion in MuSCs we further demonstrated that the massive activation of canonical Wnt signaling in MuSC following APC loss results in defective cell cycle progression and apoptosis. Mechanistically, we observed that Wnt/ß-catenin signaling orchestrates the cytoplasmic relocalization of the histone 3 lysine 9 methyltransferase Setdb1 during differentiation. We further showed that Setdb1 is required for MuSCs amplification and suppresses myoblast terminal differentiation. Genome-wide analyses showed a Wnt3a-dependant release of Setdb1 from the promoter of selected target genes upon myoblast terminal differentiation. Taken together, our results demonstrate that both canonical and non-canonical Wnt pathways are necessary for MuSC function. Lastly, I will discuss the potential cross-talks between these two faces of an important signaling.

Annonce de séminaire


Mercredi 5 Octobre à 11:00 – Salle Guillermond, Bâtiment L’Herbier, 9 rue Raphaël Dubois

Stefan Dimitrov

Institut Albert Bonniot, Centre de Recherche UGA – INSERM U1209 / CNRS UMR 5309, Grenoble, France.

Epigenetic strategies : nucleosome remodeling, histone modifications and histone variants.

Invité par Laurent Schaeffer

Abstract
Chromatin impedes the binding of protein factors to the underlying DNA sequences. The cell uses three main “epigenetic tools” to overcome the chromatin barrier, namely, chromatin remodelers, histone variants and histone post-translational modifications. We will give specific examples of how either one of these “epigenetic tools” functions.
Chromatin remodelers are sophisticated nano-machines, which are able to alter histone-DNA interactions and to mobilize nucleosomes. Neither the mechanism of their action nor the conformation of the remodeled nucleosomes are, however, yet well understood. We have studied the mechanism of RSC-induced chromatin remodeling by using high resolution microscopy and state of the art biochemistry techniques. The data illustrates how RSC remodels the nucleosome in vitro and shed light on its in vivo function. The crystal structure of the CENP-A nucleosome was recently solved. Intriguingly, in contrast to the canonical nucleosome (where 147 bp of DNA are wrapped around the histone octamer), only the central 121 bp were visible, suggesting flexible CENP-A nucleosomal ends. Why the CENP-A nucleosome exhibits flexible DNA ends is totally unknown. Our data show that the flexible DNA ends of the CENP-A nucleosome are required for mitotic fidelity.
The Aurora family of oncogenic kinase consists of two major members, Aurora A and Aurora B. Both kinases exhibit very high homology. They show, however, quite distinct localization and function. Histone H3 is specifically phosphorylated, presumably by the oncogenic kinase Aurora B, at serine 10 at the onset of mitosis. Here we will present data on the distinct function of the two Aurora kinases and the mechanism of phosphorylation of histone H3 by Aurora B.

Annonce de séminaire

Vendredi 7 Octobre à 14:00 – Amphithéâtre CNRS

Stéphane Vassilopoulos

Institut de Myologie, UMRS 974 UPMC-Inserm / FRE 3617 CNRS, G. H. Pitié-Salpétrière, Paris – France.

The endocytic machinery in healthy and diseased muscle

Invité par Laurent Schaeffer

Abstract
Costameres represent specialized focal adhesion sites of muscle fibres, located between the plasma membrane and sarcomeres, the contractile units of muscle. When disrupted, they directly contribute to the development of several distinct myopathies.
We have shown that the ubiquitous clathrin heavy chain (CHC), well characterized for its role in intracellular membrane traffic and endocytosis from the plasma membrane (PM), forms large plaques connected to α-actinin and actin filaments. Depletion of CHC leads to defective costamere formation and maintenance both in vitro and in vivo and induces sarcomere disorganization and a loss of contractile force due to the detachment of sarcomeres from the PM. At costameres, CHC is co-expressed with dynamin 2 (DNM2), another key protein of the intracellular membrane trafficking machinery which is mutated in autosomal dominant centronuclear myopathy (CNM). We analyzed the role of DNM2 and several actin binding proteins on clathrin plaque function at costameres in vitro by using either siRNA depletion combined to high resolution electron microscopy or in vivo by intravital microscopy. We also focused on the possible link between costamere and CNM pathophysiology. Using myoblasts from DNM2-mutated patients and using myoblasts and muscles from a knock-in mouse model of DNM2-related myopathy, we analyzed structure of costameres by biochemical and immunocytochemical approaches, as well as their ultrastructure.
Our results demonstrate a crucial role for the endocytic machinery and the cytoskeleton. Their contribution to the formation and maintenance of the contractile apparatus highlight an unconventional role for clathrin flat lattices in skeletal muscle which may be relevant to pathophysiology of several neuromuscular disorders.

Annonce de séminaire

Septembre 2016

Vendredi 30 Septembre à 11:00 – Amphithéâtre CNRS

Sandrine Humbert

GIN – Inserm U1216 – University Grenoble Alpes, Grenoble, France.

Huntingtin regulates cortical development: consequences for Huntington’s disease

Invité par Julien Courchet

Abstract
The bulk of interest in the huntingtin protein has centered on the fact that, when mutated, huntingtin causes Huntington’s disease (HD), a devastating neurodegenerative disorder. The mutation causing HD is an abnormal polyglutamine stretch in huntingtin. Given the adult onset and dysfunction and death of adult neurons characterizing HD, most studies have focused on the toxic effects elicited by mutant huntingtin in post-mitotic neurons. However, the protein is ubiquitous and expressed in the developing embryo where it plays an essential role as revealed by the early embryonic lethality at day 7.5 of the complete knockout of the huntingtin gene in mouse. Anyway, the roles of the wild-type protein during development have been overlooked. I will discuss how huntingtin regulates several steps of mouse embryonic corticogenesis. I will also show the consequences of the presence of an abnormal polyglutamine expansion in huntingtin during cortical neurogenesis and consider the viewing of HD as a developmental disorder.

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July 2016

Mardi 12 juillet a 11:00 – Amphithéâtre CNRS

Jan Tuckermann

Institute of Comparative Molecular Endocrinology Ulm University, Ulm, Germany.

Modes of GR action revised – Novel mechanisms of corticosteroids in inflammation and bone integrity

Invited by Bénédicte Chazaud

Abstract
The Tuckerman Laboratory made major contributions to the molecular mechanisms of corticosteroids in beneficial and side effects of steroid therapy. With the help of conditional and function-selective knockout mice for the glucocorticoid receptor (GR) the lab identified critical cell types and novel mechanisms for anti-inflammatory activities of glucocorticoids in different inflammatory disease models. Furthermore we made the discovery that in a model of lung inflammation the anti-inflammatory action of glucocorticoids is not dependent on the inhibition of pro-inflammatory mediators, but rather requires cooperation with pro-inflammatory signaling pathways (e.g. p38) to induce anti-inflammatory acting genes and alternative polarization of macrophages.

Annonce de séminaire


Juin 2016

Vendredi 24 juin à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Pierre-Jean Corringer

Pasteur Institute, Channel-receptor Unit, CNRS UMR 3571, 25 rue du Docteur Roux, 75015 Paris, France.

Pentameric ligand-gated ion channels functioning at the atomic resolution

Invited by Maëlle Jospin

Abstract
Pentameric channel-receptors, including nicotinic acetylcholine, glycine and GABAA receptors, play a key role in fast excitatory and inhibitory transmission in the nervous system and are the target of numerous therapeutic and addictive drugs. They carry several neurotransmitter binding sites which govern the opening of a transmembrane ion channel. Extensively expressed in animals, they were found in several bacteria, especially the homolog from the cyanobacteria Gloeobacter violaceus (GLIC) which functions as a proton-gated ion channel. The simplified architecture of this archaic homologue, as well as its prokaryotic origin, allowed solving its X-ray structure in several conformations. Those static structures suggest that channel opening occurs through symmetrical quaternary twist and “blooming” motions, together with tertiary deformation. We further engineered multiple fluorescent reporters on the structure, allowing investigating the dynamics of the allosteric reorganizations and showing that activation involves a key pre-active conformation. Finally, the GLIC system was exploited to solve the structure of human receptors through the generation of functional chimeras. Overall, our work gives insights into the mechanism of gating and pharmacological regulation of this important family of neurotransmitter receptors.


Mai 2016

 

Lundi 30 mai à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Yishi Jin

UC San Diego.

Mechanisms regulating synapse maintenance and neural activity

Invited by Jean-Louis Bessereau

Abstract
Synapses are organized subcellular structures that transmit information within the nervous system and to other parts of our body. Our studies use C. elegans have uncovered multiple pathways controlling synapse formation, maintenance and function. Using a genetic model mimicking the physiological state of seizures, our recent work have identified novel regulatory themes affecting presynaptic release machinery. We also discovered that a novel immunoglobulin superfamily (IgSF) transmembrane protein mediates synapse and non-neuronal tissue interaction in synapse maintenance. These findings have implications to our understanding of circuit malfunction under disease conditions.

Annonce de séminaire


Jeudi 26 mai à 11:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Francesco Zorzato

Department of Biomedicine, Basel University

Pathophysiology of ryanodinopathies

Invited by Bruno Allard

Abstract
Type 1 ryanodine receptor (RyR1) is preferentially expressed in skeletal muscle, and mutations in the gene have been associated with malignant hyperthermia, a pharmacogenetic disease, and with several congenital myopathies, including central core disease, multiminicore disease, centronuclear myopathy, congenital fibre type disproportion. Experimental data have indicated that RyR1 is also expressed in some areas of the central nervous system, in some cell types of the immune system and in smooth muscle cells. These results imply that mutations in the gene encoding RyR1 will not only affect skeletal muscles, but other tissues that express this calcium channel as well, thereby broadening the clinical spectrum of disorders due to RyR1 dysfunctions.
The RyR1 is of fundamental importance for the development of muscle force and a decrease in its content may be causally linked to the profound muscle weakness seen in patients with some forms of congenital myopathies linked to recessive RYR1 mutations. The protein composition of the junctional sarcoplasmic reticulum membrane encompassing the excitation-contraction coupling molecular complex (ECCMC) is extremely complicated. Polymorphic variants of the junctional sarcoplasmic reticulum protein JP45 have been shown to segregate in Malignant Hyperthermia Susceptible subjects of Malignant Hyperthermia families in the UK. Thus, some ECCMC accessory proteins may play a role not only in regulating excitation-contraction coupling but also as modifiers of the ryanodinopathies phenotype.

Annonce de séminaire

 


 

Jeudi 19 mai à 11:00 – Amphithéâtre de la délégation du CNRS

Dr. Jean-Marc Goaillard

UNIS – Aix Marseille Université

Biophysical networks underlying electrical phenotype of dopaminergic neurons

Invited by Thomas Boulin

Abstract
Any type of neurons can be easily identified based on its electrophysiological activity, such as its pattern of spontaneous activity, the shape of its action potential, its dendritic integration, etc. How is stability of such electrical phenotype achieved, what are its molecular principles, and what is the degree of robustness of electrical phenotype in the face of different perturbations are questions only very partially answered. We studied these questions on dopaminergic neurons of the substantia nigra pars compacta. Our work involved characterizing the electrical phenotype of these neurons and measuring its post-natal development and its stability at mature stages. We also characterized the specific relationships of electrophysiological parameters underlying the electrical phenotype. In order to determine how complex electrical phenotype is achieved, we then investigated the networks of co-regulation of ion channels at the genetic and at the protein levels. Our results suggest that ion channel gene expression and protein interactions display a modular structure that may be involved in stabilizing phenotype. We also show that electrical phenotype also presents such a modular structure. Our ultimate goal is to provide a systems-level approach to robustness of electrical phenotype.

Annonce de séminaire

 


 

Vendredi 13 mai à 14:00 – Salle Guillermond – Bâtiment l’Herbier

Dr. Michele Zoli

 


Avril 2016

Friday Avril 29th at 14:00 – Amphithéâtre de la délégation du CNRS

Dr. Shiva Tyagarajan

Inst. of Pharmacology and Toxicology, University of Zurich.

Interrupting neuronal communication from a GABAergic viewpoint

Invited by Jean-Louis Bessereau

Abstract
In the brain distinct population of inhibitory GABAergic interneurons innervate principal glutamatergic neurons to regulate various aspects of brain function. At the postsynaptic compartment, specific GABAAR subunits are segregated to different neuronal compartments to recieve specific inputs from different interneurons. The correct interpretation of the incoming signal requires functional coupling between the presynaptic neurotransmitter GABA, postsynaptic GABAARs, and downstream signaling by postsynaptic density proteins. The main postsynaptic density protein at inhibitory synapse is gephyrin. In the past decade we have identified diverse signaling cascades that converge on gephyrin scaffold to regulate its scaffolding property, and in turn GABAergic neurotransmission. These studies have shed light into mechanisms that underlie dynamic changes in inhibitory neurotransmission, and how excitation shapes inhibition.

Annonce de séminaire

Janvier 2016

Vendredi 29 janvier à 14:00 – Bâtiment l’Herbier

Pura Muñoz-Cànoves

ICREA Research Professor at Universitat Pompeu Fabra, Barcelona.

Tissue regenerative decline with aging: focus on muscle stem cells

Invited by Bénédicte Chazaud

Abstract
Our group aims to understand the mechanisms regulating stem cell homeostasis and regenerative functions. Research is specially centered on stem cells of skeletal muscle (i.e., satellite cells). Recently, we have focused on two areas: 1) the functional decline of satellite cells with aging; and 2) the physiopathology of muscular dystrophies, with a specific interest in the contribution of inflammation and fibrosis to dystrophy progression. Concerning the first area, work from different laboratories has demonstrated that both environmental and cell- autonomous signals alter satellite cell regenerative potential with aging. I will discuss our latest results showing that satellite cells in their homeostatic quiescent state are equipped with quality control mechanisms to preserve their fitness, and how age-associate alterations in these protective mechanisms lead to stem cell loss of function and regenerative capacity.

Annonce de séminaire