Synapses are sophisticated nanomachines that support transfer and processing of information between excitable cells. Since most neurons receive thousands of synaptic inputs, the neuronal membrane is a mosaic of specialized microdomains where neurotransmitter receptors cluster in register with the corresponding presynaptic neurotransmitter release sites. Our lab is interested in identifying the cellular and molecular mechanisms involved in the organization and maintenance of the synapse with a specific focus on the control of neurotransmitter receptor expression and localization.
Our strategy is based on the combination of genetics, imaging, electrophysiology and biochemistry in the nematode Caenorhabditis elegans (for more information on C. elegans see "an overview of the model organism C. elegans"). Using the neuromuscular synapse as a model synapse, we identified several new genes involved in the clustering of acetylcholine and GABAA receptors through previously undescribed mechanisms, including a novel anterograde synaptic organizer that assembles extracellular scaffolds in the synaptic cleft. We are currently analyzing the organization, dynamics and maintenance of these synaptic scaffolds as well as the genes involved in the biosynthesis and trafficking of the receptors.
Our results should contribute to a better understanding of the normal and pathological synapse. Specifically, synaptic defects have been involved over the last years in the pathogenesis of a growing number of neuropsychiatric diseases, leading to the concept of "synaptopathies". However, a number of genes linked to neuropsychiatric diseases have no assigned function, and it is likely that the mutational landscape of these diseases will be complexified by the wealth of data generated with next generation sequencing techniques. Simple organisms should help!
2019 Internship – Masters level
Genetic control of acetylcholine receptor biosynthesis: from C. elegans to human pathologies.
Dysfunction of acetylcholine receptors is linked to several pathologies, including myasthenia or schizophrenia. The quantity of the receptors at the plasma membrane is thus finely tuned and results from a balance between biosynthesis, recycling and degradation of the receptors. The aim of the internship is to characterize the role of two proteins, TMED7 and TMED2, in the biogenesis of the receptors.
- UNC-120/SRF independently controls muscle aging and lifespan in Caenorhabditis elegans.
Mergoud Dit Lamarche A, Molin L, Pierson L, Mariol MC, Bessereau JL, Gieseler K, Solari F Aging Cell (2018) 17.
- Preventing Illegitimate Extrasynaptic Acetylcholine Receptor Clustering Requires the RSU-1 Protein.
Pierron M, Pinan-Lucarré B, Bessereau JL J Neurosci. (2016) 36:6525-37.
- C. elegans Punctin Clusters GABA(A) Receptors via Neuroligin Binding and UNC-40/DCC Recruitment.
Tu H, Pinan-Lucarré B, Ji T, Jospin M, Bessereau JL Neuron (2015) 86:1407-19.
- Transcriptional coordination of synaptogenesis and neurotransmitter signaling.
Kratsios P, Pinan-Lucarré B, Kerk SY, Weinreb A, Bessereau JL, Hobert O Curr Biol. (2015) 25:1282-95.
- C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains.
Pinan-Lucarré B, Tu H, Pierron M, Cruceyra PI, Zhan H, Stigloher C, Richmond JE, Bessereau JL Nature (2014) 511:466-70.
- Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex.
Richard M, Boulin T, Robert VJ, Richmond JE, Bessereau JL Proc Natl Acad Sci U S A. (2013) 110: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 Nat Neurosci. (2012) 15:1374-81.
- A secreted complement-control-related protein ensures acetylcholine receptor clustering.
Gendrel M, Rapti G, Richmond JE, Bessereau JL Nature (2009) 15:992-6.
- Eight genes are required for functional reconstitution of the Caenorhabditis elegans levamisole-sensitive acetylcholine receptor.
Boulin T, Gielen M, Richmond JE, Williams DC, Paoletti P, Bessereau JL Proc Natl Acad Sci U S A. (2008) 25:18590-5.
- A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans.
Gally C, Eimer S, Richmond JE, Bessereau JL Nature (2004) 30:578-82.