Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning

Yun Liu, Daniel Padgett, Masazumi Takahashi, Hongqiao Li, Ayaz Sayeed, Russell W. Teichert, Baldomero M. Olivera, Joseph J. McArdle, William N. Green, Weichun Lin

Research output: Contribution to journalArticle

40 Scopus citations

Abstract

Formation of the vertebrate neuromuscular junction (NMJ) takes place in a stereotypic pattern in which nerves terminate at select sarcolemmal sites often localized to the central region of the muscle fibers. Several lines of evidence indicate that the muscle fibers may initiate postsynaptic differentiation independent of the ingrowing nerves. For example, nascent acetylcholine receptors (AChRs) are pre-patterned at select regions of the muscle during the initial stage of neuromuscular synaptogenesis. It is not clear how these pre-patterned AChR clusters are assembled, and to what extent they contribute to pre-and post-synaptic differentiation during development. Here, we show that genetic deletion of the AChR γ-subunit gene in mice leads to an absence of pre-patterned AChR clusters during initial stages of neuromuscular synaptogenesis. The absence of pre-patterned AChR clusters was associated with excessive nerve branching, increased motoneuron survival, as well as aberrant distribution of acetylcholinesterase (AChE) and rapsyn. However, clustering of muscle specific kinase (MuSK) proceeded normally in the γ-null muscles. AChR clusters emerged at later stages owing to the expression of the AChR epsilon-subunit, but these delayed AChR clusters were broadly distributed and appeared at lower level compared with the wild-type muscles. Interestingly, despite the abnormal pattern, synaptic vesicle proteins were progressively accumulated at individual nerve terminals, and neuromuscular synapses were ultimately established in γ-null muscles. These results demonstrate that the γ-subunit is required for the formation of pre-patterned AChR clusters, which in turn play an essential role in determining the subsequent pattern of neuromuscular synaptogenesis.

Original languageEnglish (US)
Pages (from-to)1957-1967
Number of pages11
JournalDevelopment
Volume135
Issue number11
DOIs
StatePublished - Jun 1 2008

Keywords

  • Neuromuscular junction
  • Nicotinic acetylcholine receptor
  • Synaptic patterning
  • Synaptogenesis

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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    Liu, Y., Padgett, D., Takahashi, M., Li, H., Sayeed, A., Teichert, R. W., Olivera, B. M., McArdle, J. J., Green, W. N., & Lin, W. (2008). Essential roles of the acetylcholine receptor γ-subunit in neuromuscular synaptic patterning. Development, 135(11), 1957-1967. https://doi.org/10.1242/dev.018119