Pierron Marie, Pinan-Lucarré Bérangère, Bessereau Jean-Louis
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.
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
J Neurosci. 2016 Jun 15;36(24):6525-37. doi: 10.1523/JNEUROSCI.3733-15.2016.
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.
弥漫性突触外神经递质受体构成了一个丰富的受体库，可被募集来调节突触强度。突触外膜中受体的弥漫性分布究竟是一种默认状态还是受到主动控制，基本上仍不清楚。在此我们表明，秀丽隐杆线虫肌肉细胞中突触外乙酰胆碱受体（AChRs）的正确分布需要RSU-1（Ras抑制因子-1）。RSU-1是一种进化保守的细胞质蛋白，含有多个富含亮氨酸的重复序列（LRRs），并与整合素依赖性黏附复合物相互作用。在rsu-1突变体中，神经肌肉接头的分化与野生型相同，但AChRs组装成异位簇，在发育过程中逐渐扩大。结果，AChRs的突触含量减少。我们的研究提供了首个证据，表明一种依赖RSU-1的主动机制可维持突触外受体的分散状态，并间接调节突触成熟。
以秀丽隐杆线虫神经肌肉接头作为模型突触，我们发现了一种调节乙酰胆碱受体（AChRs）分布的新机制。在对AChR分布异常的突变体进行的无偏视觉筛选中，我们基于大型突触外簇的存在分离出了ras抑制因子1（rsu-1）突变体。我们表明，破坏rsu-1会导致通常分散的突触外受体自发聚集，且与突触信号无关。这些簇胜过突触区域，导致突触受体含量减少。这些结果表明，突触外受体的弥漫状态不是一种仅由缺乏突触信号就能简单解释的默认状态，而是需要额外的蛋白质来防止自发聚集，这一概念与发育和病理情况相关。
