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!
- 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) in press.
- Biallelic mutation of UNC50, encoding a protein involved in AChR trafficking, is responsible for arthrogryposis.
Abiusi E, D'Alessandro M, Dieterich K, Quevarec L, Turczynski S, Valfort AC, Mezin P, Jouk PS, Gut M, Gut I, Bessereau JL, Melki J Hum Mol Genet (2017) 26:3989-94.
- Preventing Illegitimate Extrasynaptic Acetylcholine Receptor Clustering Requires the RSU-1 Protein.
Pierron M, Pinan-Lucarré B, Bessereau JL J Neurosci (2016) 36:6525-37.
- Filling the gap: adding super-resolution to array tomography for correlated ultrastructural and molecular identification of electrical synapses at the C. elegans connectome.
Markert SM, Britz S, Proppert S, Lang M, Witvliet D, Mulcahy B, Sauer M, Zhen M, Bessereau JL, Stigloher C Neurophotonics (2016) 3:041802.
- C. elegans Punctin clusters GABAA receptors via neuroligin binding and UNC-40/DCC recruitment.
Tu H*, Pinan-Lucarré B*, Ji T, Jospin M, Bessereau J-L Neuron (2015) 86:1407-19.
- Transcriptional coordination of synaptogenesis and neurotransmitter signaling.
Kratsios P, Pinan-Lucarré B, Kerk SY, Weinreb A, Bessereau J-L, Hobert O Current Biology (2015) 25:1282-95.
- C. elegans Punctin specifies cholinergic versus GABAergic identity of postsynaptic domains.
Pinan-Lucarre B*, Tu H*, Pierron M, Ibáñez Cruceyra P, Zhan H, Stigloher C, Richmond J, Bessereau JL Nature (2014) 511: 466-70.
- Metabolomics analysis uncovers that dietary restriction buffers metabolic changes associated with aging in Caenorhabditis elegans.
Pontoizeau C, Mouchiroud L, Molin L, Mergoud-Dit-Lamarche A, Dalliere N, Toulhoat P, Elena-Herrmann B, Solari F J Proteome Res. (2014) 13:2910-9.
- 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 USA (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 single immunoglobulin-domain protein required for clustering acetylcholine receptors in C. elegans.
Rapti G, Richmond J, Bessereau JL EMBO J. (2011) 30:706-18.
- The presynaptic dense projection of the Caenorhabditis elegans cholinergic neuromuscular junction localizes synaptic vesicles at the active zone through SYD-2/liprin and UNC-10/RIM-dependent interactions.
Stigloher C, Zhan H, Zhen M, Richmond J, Bessereau JL J Neurosci. (2011) 31:4388-96.
- Insulin/Insulin-like growth factor signaling controls non-Dauer developmental speed in the nematode Caenorhabditis elegans.
Ruaud AF, Katic I, Bessereau JL Genetics (2011) 187:337-43.
- A secreted complement-control-related protein ensures acetylcholine receptor clustering.
Gendrel M, Rapti G, Richmond JE, Bessereau JL Nature (2009) 461:992-6.
- 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 Biol. (2009) 7:e1000265. .