title: Muscle Yap Is a Regulator of Neuromuscular Junction Formation and Regeneration.
abstract: 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). InHSA-Yap-/-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,HSA-Yap-/-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 ofHSA-Yap-/-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.SIGNIFICANCE STATEMENTThis 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 ofHSA-Yap-/-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.
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Kai
authors.identifier: 0000-0003-2363-1297
authors.initials: K
authors.lastname: Zhao
authors.affiliation: 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.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Shen
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Department of Physiology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan 430070, China.|Institute of Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430070, China.
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Institute of Hypoxia Medicine and Institute of Neuroscience, Wenzhou Medical University, Wenzhou 325035, China.
authors.forename: Zhihui
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: Aurora Scientific Inc., Aurora, Ontario L4G 1X6, Canada, and.
authors.forename: Christopher D
authors.identifier: 0000-0003-2780-5565
authors.initials: CD
authors.lastname: Rand
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912.
authors.forename: Jinxiu
authors.identifier: 0000-0003-4013-1390
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Xiang-Dong
authors.identifier: 0000-0002-0051-1463
authors.initials: XD
authors.lastname: Sun
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Zhibing
authors.identifier: 0000-0002-1541-3479
authors.initials: Z
authors.lastname: Tan
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Hongsheng
authors.identifier: 0000-0003-3190-3280
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Guanglin
authors.identifier: 0000-0002-8258-0293
authors.initials: G
authors.lastname: Xing
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Yu
authors.identifier: 0000-0003-0067-5422
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Guoqing
authors.initials: G
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.
authors.forename: Jiliang
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912.
authors.forename: Wen-Cheng
authors.initials: WC
authors.lastname: Xiong
authors.affiliation: Department of Neuroscience and Regenerative Medicine, Medical College of Georgia, Augusta University, Augusta, Georgia 30912, lmei@augusta.edu.|Department of Neurology, Medical College of Georgia, Augusta University, Augusta, Georgia 30912.|Charlie Norwood Veterans Administration Medical Center, Augusta, Georgia 30912.
authors.forename: Lin
authors.identifier: 0000-0001-5772-1229
authors.initials: L
authors.lastname: Mei
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053580:Muscle Strength / Q000502:physiology*; D018482:Muscle, Skeletal / Q000294:innervation / Q000502:physiology*; D009416:Nerve Regeneration / Q000502:physiology*; D009469:Neuromuscular Junction / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D011950:Receptors, Cholinergic / Q000378:metabolism; D009435:Synaptic Transmission / Q000502:physiology*; D060449:Wnt Signaling Pathway / Q000502:physiology; D000091102:YAP-Signaling Proteins; D051176:beta Catenin / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C495267:CTNNB1 protein, mouse; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D011950:Receptors, Cholinergic; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D051176:beta Catenin
keywords: YAP; neuromuscular junction; regeneration; β-catenin