Increased neuromuscular activity causes axonal defects and muscular degeneration

Julie L. Lefebvre, Fumihito Ono, Cristina Puglielli, Glen Seidner, Clara Franzini-Armstrong, Paul Brehm, Michael Granato

Research output: Contribution to journalArticlepeer-review

58 Scopus citations


Before establishing terminal synapses with their final muscle targets, migrating motor axons form en passant synaptic contacts with myotomal muscle. Whereas signaling through terminal synapses has been shown to play important roles in pre- and postsynaptic development, little is known about the function of these early en passant synaptic contacts. Here, we show that increased neuromuscular activity through en passant synaptic contacts affects pre- and postsynaptic development. We demonstrate that in zebrafish twister mutants, prolonged neuromuscular transmission causes motor axonal extension and muscular degeneration in a dose-dependent manner. Cloning of twister reveals a novel, dominant gain-of-function mutation in the muscle-specific nicotinic acetylcholine receptor α-subunit, CHRNA1. Moreover, electrophysiological analysis demonstrates that the mutant subunit increases synaptic decay times, thereby prolonging postsynaptic activity. We show that as the first en passant synaptic contacts form, excessive postsynaptic activity in homozygous embryos severely impedes pre- and postsynaptic development, leading to degenerative defects characteristic of the human slow-channel congenital myasthenic syndrome. By contrast, in heterozygous embryos, transient and mild increase in postsynaptic activity does not overtly affect postsynaptic morphology but causes transient axonal defects, suggesting bi-directional communication between motor axons and myotomal muscle. Together, our results provide compelling evidence that during pathfinding, myotomal muscle cells communicate extensively with extending motor axons through en passant synaptic contacts.

Original languageEnglish (US)
Pages (from-to)2605-2618
Number of pages14
Issue number11
StatePublished - Jun 2004
Externally publishedYes


  • Acetylcholine receptor α-subunit
  • En passant terminals
  • Motor axon
  • Slow-channel congenital myasthenic syndrome
  • Synaptogenesis
  • Zebrafish
  • chrna1
  • nic1
  • twister

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology


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