Muscle Yap Is a Regulator of Neuromuscular Junction Formation and Regeneration.

Publisher: Society for Neuroscience Country of Publication: United States NLM ID: 8102140 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1529-2401 (Electronic) Linking ISSN: 02706474 NLM ISO Abbreviation: J Neurosci Subsets: MEDLINE

Publication: Washington, DC : Society for Neuroscience
Original Publication: [Baltimore, Md.] : The Society, c1981-

Adaptor Proteins, Signal Transducing/*metabolism ; Muscle Strength/*physiology ; Muscle, Skeletal/*physiology ; Nerve Regeneration/*physiology ; Neuromuscular Junction/*physiology ; Phosphoproteins/*metabolism ; Synaptic Transmission/*physiology; Animals ; Cell Cycle Proteins ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Muscle, Skeletal/innervation ; Receptors, Cholinergic/metabolism ; Wnt Signaling Pathway/physiology ; YAP-Signaling Proteins ; beta Catenin/metabolism

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 HSA-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 of HSA-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 STATEMENT 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 HSA-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.
(Copyright © 2017 the authors 0270-6474/17/373465-13$15.00/0.)

Erratum in: J Neurosci. 2017 May 3;37(18):4859. (PMID: 28469011)

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R01 HL109605 United States HL NHLBI NIH HHS

Keywords: YAP; neuromuscular junction; regeneration; β-catenin

0 (Adaptor Proteins, Signal Transducing)
0 (CTNNB1 protein, mouse)
0 (Cell Cycle Proteins)
0 (Phosphoproteins)
0 (Receptors, Cholinergic)
0 (YAP-Signaling Proteins)
0 (Yap1 protein, mouse)
0 (beta Catenin)

Date Created: 20170219 Date Completed: 20170818 Latest Revision: 20211204

20231215

PMC5373129

10.1523/JNEUROSCI.2934-16.2017

28213440