Preventing Illegitimate Extrasynaptic Acetylcholine Receptor Clustering Requires the RSU-1 Protein.
Diffuse extrasynaptic neurotransmitter receptors constitute an abundant pool of receptors that can be recruited to modulate synaptic strength. Whether the diffuse distribution of receptors in extrasynaptic membranes is a default state or is actively controlled remains essentially unknown. Here we show that RSU-1 (Ras Suppressor-1) is required for the proper distribution of extrasynaptic acetylcholine receptors (AChRs) in Caenorhabditis elegans muscle cells. RSU-1 is an evolutionary conserved cytoplasmic protein that contains multiple leucine-rich repeats (LRRs) and interacts with integrin-dependent adhesion complexes. In rsu-1 mutants, neuromuscular junctions differentiate as in the wild type, but AChRs assemble into ectopic clusters that progressively enlarge during development. As a consequence, the synaptic content of AChRs is reduced. Our study provides the first evidence that an RSU-1-dependent active mechanism maintains extrasynaptic receptors dispersed and indirectly regulates synapse maturation.



Using Caenorhabditis elegans neuromuscular junction as a model synapse, we uncovered a novel mechanism that regulates the distribution of acetylcholine receptors (AChRs). In an unbiased visual screen for mutants with abnormal AChR distribution, we isolated the ras suppressor 1 (rsu-1) mutant based on the presence of large extrasynaptic clusters. We show that disrupting rsu-1 causes spontaneous clustering of extrasynaptic receptors that are normally dispersed, independently of synaptic cues. These clusters outcompete synaptic domains and cause a decrease of synaptic receptor content. These results indicate that the diffuse state of extrasynaptic receptors is not a default state that is simply explained by the lack of synaptic cues but necessitates additional proteins to prevent spontaneous clustering, a concept that is relevant for developmental and pathological situations.
Institut NeuroMyoGene, Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5310, Institut National de la Santé et de la Recherche Médicale U1217, 69622 Villeurbanne, France.
Marie
M
Pierron
Institut NeuroMyoGene, Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5310, Institut National de la Santé et de la Recherche Médicale U1217, 69622 Villeurbanne, France.
Bérangère
B
Pinan-Lucarré
Institut NeuroMyoGene, Université Claude Bernard Lyon 1, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 5310, Institut National de la Santé et de la Recherche Médicale U1217, 69622 Villeurbanne, France jean-louis.bessereau@univ-lyon1.fr.
Jean-Louis
JL
Bessereau
D000818:Animals; D030801:Animals, Genetically Modified; D000906:Antibodies / Q000494:pharmacology; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D009469:Neuromuscular Junction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D011950:Receptors, Cholinergic / Q000276:immunology / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism
D000906:Antibodies; D029742:Caenorhabditis elegans Proteins; D002352:Carrier Proteins; D009124:Muscle Proteins; D011950:Receptors, Cholinergic; D014157:Transcription Factors; D033921:Vesicular Transport Proteins; C000621192:rsu-1 protein, C elegans; D049452:Green Fluorescent Proteins; C076224:RSU1 protein, human
C. elegans; RSU-1; acetylcholine receptor; forward genetic screen; neuromuscular junction; synapse