Projects

Two-pore domain potassium channels (K2P) play a central role in the control of cellular excitability and the regulation of the cell’s electrical membrane potential. K2Ps have been widely conserved throughout evolution. They are polymodal ion channels that are subjected to extensive regulation by a diverse set of physical (pH, temperature, mechanical force) and biological signals (lipids, G-protein coupled receptor pathways). They are broadly expressed in excitable and non-excitable cells, and have in turn been implicated in a large spectrum of physiopathological processes, ranging from the regulation of neuronal excitability, respiratory and cardiac function to the control of cell volume, hormone secretion and cell proliferation. Recently, loss- and gain-of-function mutations in K2P channels have been directly linked to human pathologies (Birk Barel syndrome, familial migraine with aura, cardiac conduction disorder).

In contrast to many other ion channel families, comparatively little is known about the molecular and cellular processes that regulate different aspects of the cell biology of K2P channels. For instance we know only of very few factors that specifically regulate the expression, the activity and the localisation of K2P channels at the cell surface. Therefore the central question addressed by our team is: How is the number of active potassium leak channels present at the cell surface controlled in vivo?

To identify novel genes and conserved cellular processes that regulate the biology of K2P channels in vivo we take advantage of the powerful genetic tools available in the model nematode Caenorhabditis elegans. We use the full array of techniques available in C. elegans including genetics, live imaging, electrophysiology and state-of-the-art CRISPR/Cas9 genome engineering and next-generation DNA sequencing. These studies will provide new leads to understand the cellular pathways that control K2P function in other organisms.

Molecular, cellular, and clinical investigation of the autism, epilepsy, and neurodevelopmental disorder gene Neurobeachin/NBEA

ANR NBElegAns 2020-2024

Neurobeachin is a brain-specific protein required for vesicular trafficking, synaptic structure, and synaptic targeting of neurotransmitter receptors. Neurobeachin mutations have very recently been identified as a genetic cause of autism, neurodevelopmental delay and early generalized epilepsy (Mulhern et al., 2018). During a genetic screen in C. elegans, we have discovered that Neurobeachin can also regulate potassium channel trafficking. Interestingly, these channels play a central role in controlling neuronal excitability. In this project, we propose to combine clinical and fundamental research approaches to better understand the pathophysiology of this new neurological disease, identify cellular processes regulated by Neurobeachin, and find new molecular partners that could serve as potential therapeutic targets in the future.

This project will be a collaborative venture between our team, Tristan T. Sands and Natalie Lippa (Columbia University, New York), Sarah Weckhuysen (VIB & University of Antwerp), Qiang Liu (Bargmann Lab, Rockefeller University, New York), and Maëlle Jospin (Bessereau Lab, Institut NeuroMyoGène, Lyon).

If you are interested in joining the project as a Post-doctoral fellow, Masters, or PhD Student, don’t hesitate to contact us!

SELECTED PUBLICATIONS

FULL PUBLICATION LIST

• Functional analysis of a de novo variant in the neurodevelopment and generalized epilepsy disease gene NBEA.
  Boulin T, Itani O, El Mouridi S, Leclercq-Blondel A, Gendrel M, Macnamara E, Soldatos A, Murphy JL, Gorman MP, Lindsey A, Shimada S, Turner D, Silverman GA, Baldridge D; Undiagnosed Diseases Network, Malicdan MC, Schedl T, Pak SC. Molecular Genetics and Metabolism (2021).
• A single-nucleotide change underlies the genetic assimilation of a plastic trait.
  Vigne P, Gimond C, Ferrari C, Vielle A, Hallin J, Pino-Querido A, El Mouridi S, Mignerot L, Frøkjær-Jensen C, Boulin T, Teotónio H, Braendle C. Science Advances (2021).
• Mutation of a single residue promotes gating of vertebrate and invertebrate two-pore domain potassium channels.
  Ben Soussia I, El Mouridi S, Kang D, Leclercq-Blondel A, Khoubza L, Tardy P, Zariohi N, Gendrel M, Lesage F, Kim EJ, Bichet D, Andrini O, Boulin T. Nature Communications (2019) Feb 15;10(1):787.
• CRELD1 is an evolutionarily-conserved maturational enhancer of ionotropic acetylcholine receptors.
  D’Alessandro M, Richard M, Stigloher C, Gache V, Boulin T, Richmond JE, Bessereau JL. Elife (2018) Nov 7;7. pii: e39649.
• Reliable CRISPR/Cas9 Genome Engineering in Caenorhabditis elegans Using a Single Efficient sgRNA and an Easily Recognizable Phenotype.
  El Mouridi S, Lecroisey C, Tardy P, Mercier M, Leclercq-Blondel A, Zariohi N, Boulin T. G3 (Bethesda) (2017) May 5;7(5):1429-1437.
• Microtubule severing by the katanin complex is activated by PPFR-1-dependent MEI-1 dephosphorylation.
  Gomes JE, Tavernier N, Richaudeau B, Formstecher E, Boulin T, Mains PE, Dumont J, Pintard L. Journal of Cell Biology (2013) Aug 5;202(3):431-9.
• Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex.
  Richard M, Boulin T, Robert VJ, Richmond JE, Bessereau JL. PNAS (2013) Mar ;110(11):E1055-63.
• Positive modulation of a Cys-loop acetylcholine receptor by an auxiliary transmembrane subunit.
  Boulin T, Rapti G, Briseño-Roa L, Stigloher C, Richmond JE, Paoletti P, Bessereau JL. Nature Neuroscience (2012) Oct ;15(10):1374-81.
• Functional reconstitution of Haemonchus contortus acetylcholine receptors in Xenopus oocytes provides mechanistic insights into levamisole resistance.
  Boulin T*, Fauvin A*, Charvet C, Cortet J, Cabaret J, Bessereau JL, Neveu C. British Journal of Pharmacology (2011) Nov ;164(5):1421-32.
• A neuronal acetylcholine receptor regulates the balance of muscle excitation and inhibition in Caenorhabditis elegans.
  Jospin M, Qi YB, Stawicki TM, Boulin T, Schuske KR, Horvitz HR, Bessereau JL, Jorgensen EM, Jin Y. PLoS Biology (2009) Dec ;7(12):e1000265.

AVAILABLE POSITIONS

We are always looking for highly motivated Post-docs, Masters and PhD students to participate in our ERC Starting Grant-funded projects.
Please consult this page

GENERAL INFORMATION

Directions and further information can be found on our team web site: www.excitingworms.eu.

Financements

• Agence Nationale de la Recherche 2020-2024 – “Molecular, cellular, and clinical investigation of the autism, epilepsy, and neurodevelopmental disorder gene Neurobeachin/NBEA”
• AFM Téléthon 2016-2021 – Alliance MyoNeurALP
• Fondation Maladies Rares 2019-2020 – “Modeling disease-causing mutations of Neurobeachin/NBEA in the nematode Caenorhabditis elegans”
  

AWARDS

21st International C. elegans conference.
Posters, check! Talk, check! 30 wrmScarlet vectors gone in 3 min, check! 70+ requests to be sent out in the coming days, pending…
And to top it off, Sonia wins the Dr. Matthew J. Buechner Tie Award for service to the community!

July 6, 2017

“Genes to Genomes” announces #Worm17 GSA Poster Award Winners