Department of Biochemistry, The Hong Kong University of Science and Technology, Clear Water Bay, Hong Kong SAR, China.
Neuron. 2010 Jan 28;65(2):204-16. doi: 10.1016/j.neuron.2010.01.012.
The maturation of neuromuscular junctions (NMJs) requires the topological transformation of postsynaptic acetylcholine receptor (AChR)-containing structures from a simple plaque to an elaborate structure composed of pretzel-like branches. This maturation process results in the precise apposition of the presynaptic and postsynaptic specializations. However, little is known about the molecular mechanisms underlying the plaque-to-pretzel transition of AChR clusters. In this study, we identify an essential role for the RhoGEF ephexin1 in the maturation of AChR clusters. Adult ephexin1(-/-) mice exhibit severe muscle weakness and impaired synaptic transmission at the NMJ. Intriguingly, when ephexin1 expression is deficient in vivo, the NMJ fails to mature into the pretzel-like shape, and such abnormalities can be rescued by re-expression of ephexin1. We further demonstrate that ephexin1 regulates the stability of AChR clusters in a RhoA-dependent manner. Taken together, our findings reveal an indispensible role for ephexin1 in regulating the structural maturation and neurotransmission of NMJs.
神经肌肉接头 (NMJ) 的成熟需要将含有突触后乙酰胆碱受体 (AChR) 的结构从简单的斑块拓扑转化为由椒盐卷饼状分支组成的精细结构。这个成熟过程导致了突触前和突触后特化结构的精确对位。然而，对于 AChR 簇的斑块到椒盐卷饼的转变的分子机制知之甚少。在这项研究中，我们发现 RhoGEF ephexin1 在 AChR 簇的成熟过程中起着至关重要的作用。成年的 ephexin1(-/-) 小鼠表现出严重的肌肉无力和 NMJ 处的突触传递受损。有趣的是，当体内 ephexin1 的表达缺失时，NMJ 无法成熟为椒盐卷饼状，并且这种异常可以通过重新表达 ephexin1 来挽救。我们进一步证明 ephexin1 以依赖 RhoA 的方式调节 AChR 簇的稳定性。总之，我们的发现揭示了 ephexin1 在调节 NMJ 的结构成熟和神经传递中的不可或缺的作用。
