Genetics and neurobiology of C. elegans

Principal investigator: Jean-Louis BESSEREAU

C. elegans | synapse | neuromuscular junction | GABA receptors | Acetylcholine receptors | aging | genetics | molecular neurobiology | electrophysiology | optogenetics | super-resolution microscopy | electron microscopy

 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!

RESTOICH - Ionotropic receptor stoichiometry: pathways and pathology


The project of our researcher Manuela D’Alessandro has been selected by ANR JCJC. We will investigate the cellular principles that govern the stoichiometric composition of AChRs, in particular through the identification of novel factors that control AChR composition and their implication in neuromuscular diseases.
The large number of neuronal AChRs subtypes, together with heterogeneity in cellular and subcellular localization, hinder the research on mechanisms controlling receptor stoichiometry using traditional biochemical strategies.
Because AChRs have been extremely conserved during evolution, we will address this question first using the nematode C. elegans as a genetically tractable system, and then in human cells. We will also use the C. elegans model to rapidly validate novel variants in genes controlling AChR assembly from undiagnosed patients and assess their severity.

Genetic control of acetylcholine receptor expression: from new mechanisms to functional genomics


Our project on genetic control of AChR expression has been selected by AFM. We will try to get a comprehensive genetic landscape of We will perform new-generation screens for decreased amount of AChR at the C. elegans neuromuscular junction based on direct visualization of the receptors in vivo. Then we will test the functional conservation of C. elegans genes for AChR biosynthesis in mammals using advanced genome manipulation in mammalian cell lines. Finally we have developed a pipeline to go back from human gene variants to C. elegans and we will assess the pathogenicity of human polymorphisms found in genes required for AChR biosynthesis. modulators and shed new light on the cell biology of AChR.

Job offers

January 3rd, 2023

– Engineer offer –
Team Bessereau

Engineer in cellular and molecular biology M/F
See full offer description here.

Team members

  • Jean-Louis BESSEREAUProfessor, UCBL, HDR
  • Allan ALCOLEIPhD Student
  • Mélissa CIZERONResearcher, INSERM
  • Manuela D’ALESSANDRO — CVResearcher, INSERM
  • Evan GOUYResearcher, HCL
  • Laure GRANGERResearch Assistant, CNRS
  • Maëlle JOSPINAssistant Professor, UCBL, HDR
  • Driss LAABIDResearch Assistant, UCBL
  • Morgane MIALONPhD Student
  • Laurent MOLINResearch Assistant, CNRS
  • Minh Dao NGUYENPhD Student
  • Liubov PATRASHPhD Student
  • Bérangère PINAN-LUCARRÉ — CVResearcher, INSERM, HDR
  • Charline ROYPhD Student
  • Florence SOLARIResearcher, INSERM, HDR

Selected publications

  1. Calcineurin-Dependent Homeostatic Response of C. elegans Muscle Cells upon Prolonged Activation of Acetylcholine Receptors
    Florin F, Bonneau B, Briseño-Roa L, Bessereau JL, Jospin M.
    Cells (2023) — Show abstract
  2. Synaptogenesis: unmasking molecular mechanisms using Caenorhabditis elegans.
    Mizumoto K, Jin Y, Bessereau JL.
    Genetics (2023) — Show abstract
  3. Adamtsl3 mediates DCC signaling to selectively promote GABAergic synapse function
    Cramer TML, Pinan-Lucarre B, Cavaccini A, Damilou A, Tsai YC, Bhat MA, Panzanelli P, Rama N, Mehlen P, Benke D, Karayannis T, Bessereau JL, Tyagarajan SK.
    Cell Reports (2023) — Show abstract
  4. Synapse Formation and Function Across Species: Ancient Roles for CCP, CUB, and TSP-1 Structural Domains.
    González-Calvo I, Cizeron M, Bessereau JL, Selimi F.
    Front Neurosci. (2022) — Show abstract
  5. An extracellular scaffolding complex confers unusual rectification upon an ionotropic acetylcholine receptor in C. elegans.
    Jospin M, Bonneau B, Lainé V, Bessereau JL.
    Proc Natl Acad Sci U S A. (2022) — Show abstract
  6. Specific heparan sulfate modifications stabilize the synaptic organizer MADD-4/Punctin at Caenorhabditis elegans neuromuscular junctions.
    Cizeron M, Granger L, Bülow HE, Bessereau JL.
    Genetics (2021) — Show abstract
  7. The HSPG Syndecan is a core organizer of cholinergic synapses.
    Zhou X, Vachon C, Cizeron M, Romatif O, Bülow HE, Jospin M, Bessereau JL.
    J Cell Biol (2021) — Show abstract
  8. The netrin receptor UNC-40/DCC assembles a postsynaptic scaffold and sets the synaptic content of GABAA receptors.
    Zhou X, Gueydan M, Jospin M, Ji T, Valfort A, Pinan-Lucarré B, Bessereau JL.
    Nature Communication (2020) — Show abstract
  9. 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) — Show abstract
  10. 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) — Show abstract
  11. Preventing Illegitimate Extrasynaptic Acetylcholine Receptor Clustering Requires the RSU-1 Protein.
    Pierron M, Pinan-Lucarré B, Bessereau JL.
    Journal of Neuroscience (2016) — Show abstract
  12. 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 (2016) — Show abstract
  13. Transcriptional coordination of synaptogenesis and neurotransmitter signaling.
    Kratsios P, Pinan-Lucarré B, Kerk SY, Weinreb A, Bessereau JL, Hobert O.
    Current Biology (2015) — Show abstract
  14. 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) — Show abstract
  15. Biosynthesis of ionotropic acetylcholine receptors requires the evolutionarily conserved ER membrane complex.
    Richard M, Boulin T, Robert VJ, Richmond JE, Bessereau JL.
    PNAS (2013) — Show abstract
  16. 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) — Show abstract
  17. A secreted complement-control-related protein ensures acetylcholine receptor clustering.
    Gendrel M, Rapti G, Richmond JE, Bessereau JL.
    Nature (2009) — Show abstract
  18. 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.
    PNAS (2008) — Show abstract
  19. A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans.
    Gally C, Eimer S, Richmond JE, Bessereau JL.
    Nature (2004) — Show abstract

Funding & Support

  • Agence Nationale de la Recherche
  • Labex CORTEX website
  • 2016-2021 AFM TéléthonAlliance MyoNeurALP
  • 2015-2021 European Research Council
AFM TéléthonAgence Nationale de la Recherche
European Research Council