Zhao Kai, Shen Chengyong, Lu Yisheng, Huang Zhihui, Li Lei, Rand Christopher D, Pan Jinxiu, Sun Xiang-Dong, Tan Zhibing, Wang Hongsheng, Xing Guanglin, Cao Yu, Hu Guoqing, Zhou Jiliang, Xiong Wen-Cheng, Mei Lin
Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
Institute of Translational Medicine, First Affiliated Hospital of Zhejiang University, Hangzhou 310020, China.
J Neurosci. 2017 Mar 29;37(13):3465-3477. doi: 10.1523/JNEUROSCI.2934-16.2017. Epub 2017 Feb 17.
Yes-associated protein (Yap) is a major effector of the Hippo pathway that regulates cell proliferation and differentiation during development and restricts tissue growth in adult animals. However, its role in synapse formation remains poorly understood. In this study, we characterized Yap's role in the formation of the neuromuscular junction (NMJ). In mice where Yap was mutated specifically in muscle cells, AChR clusters were smaller and were distributed in a broader region in the middle of muscle fibers, suggesting that muscle Yap is necessary for the size and location of AChR clusters. In addition, mice also exhibited remarkable presynaptic deficits. Many AChR clusters were not or less covered by nerve terminals; miniature endplate potential frequency was reduced, which was associated with an increase in paired-pulse facilitation, indicating structural and functional defects. In addition, muscle Yap mutation prevented reinnervation of denervated muscle fibers. Together, these observations indicate a role of muscle Yap in NMJ formation and regeneration. We found that β-catenin was reduced in the cytoplasm and nucleus of mutant muscles, suggesting compromised β-catenin signaling. Both NMJ formation and regeneration deficits of mice were ameliorated by inhibiting β-catenin degradation, further corroborating a role of β-catenin or Wnt-dependent signaling downstream of Yap to regulate NMJ formation and regeneration. This paper explored the role of Yes-associated protein (Yap) in neuromuscular junction (NMJ) formation and regeneration. Yap is a major effector of the Hippo pathway that regulates cell proliferation and differentiation during development and restricts tissue growth in adult animals. However, its role in synapse formation remains poorly understood. We provide evidence that muscle Yap mutation impairs both postsynaptic and presynaptic differentiation and function and inhibits NMJ regeneration after nerve injury, indicating a role of muscle Yap in these events. Further studies suggest compromised β-catenin signaling as a potential mechanism. Both NMJ formation and regeneration deficits of mice were ameliorated by inhibiting β-catenin degradation, corroborating a role of β-catenin or Wnt-dependent signaling downstream of Yap to regulate NMJ formation and regeneration.
Yes相关蛋白（Yap）是Hippo信号通路的主要效应因子，在发育过程中调节细胞增殖和分化，并限制成年动物的组织生长。然而，其在突触形成中的作用仍知之甚少。在本研究中，我们对Yap在神经肌肉接头（NMJ）形成中的作用进行了表征。在肌肉细胞中特异性突变Yap的小鼠中，乙酰胆碱受体（AChR）簇较小，且分布在肌纤维中部更广泛的区域，这表明肌肉Yap对于AChR簇的大小和位置是必需的。此外，这些小鼠还表现出明显的突触前缺陷。许多AChR簇未被神经末梢覆盖或覆盖较少；微小终板电位频率降低，这与成对脉冲易化增加有关，表明存在结构和功能缺陷。此外，肌肉Yap突变阻止了失神经支配的肌纤维的重新神经支配。总之，这些观察结果表明肌肉Yap在NMJ形成和再生中发挥作用。我们发现突变肌肉的细胞质和细胞核中β-连环蛋白减少，表明β-连环蛋白信号受损。通过抑制β-连环蛋白降解，小鼠的NMJ形成和再生缺陷均得到改善，进一步证实了β-连环蛋白或Yap下游的Wnt依赖性信号在调节NMJ形成和再生中的作用。本文探讨了Yes相关蛋白（Yap）在神经肌肉接头（NMJ）形成和再生中的作用。Yap是Hippo信号通路的主要效应因子，在发育过程中调节细胞增殖和分化，并限制成年动物的组织生长。然而，其在突触形成中的作用仍知之甚少。我们提供的证据表明，肌肉Yap突变会损害突触后和突触前的分化及功能，并抑制神经损伤后NMJ的再生，表明肌肉Yap在这些事件中发挥作用。进一步的研究表明，β-连环蛋白信号受损是一种潜在机制。通过抑制β-连环蛋白降解，小鼠的NMJ形成和再生缺陷均得到改善，证实了β-连环蛋白或Yap下游的Wnt依赖性信号在调节NMJ形成和再生中的作用。
