Neuromuscular development in the avian paralytic mutant crooked neck dwarf (cn/cn): Further evidence for the role of neuromuscular activity in motoneuron survival

Ronald W. Oppenheim, David Prevette, Lucien J. Houenou, Martine Pinçon-Raymond, Violetta Dimitriadou, Anne Donevan, Michael O'Donovan, Peter Wenner, David D. Mckemy, Paul D. Allen

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Neuromuscular transmission and muscle activity during early stages of embryonic development are known to influence the differentiation and survival of motoneurons and to affect interactions with their muscle targets. We have examined neuromuscular development in an avian genetic mutant, crooked neck dwarf (cn/cn), in which a major phenotype is the chronic absence of the spontaneous, neurally mediated movements (motility) that are characteristic of avian and other vertebrate embryos and fetuses. The primary genetic defect in cn/cn embryos responsible for the absence of motility appears to be the lack of excitation-contraction coupling. Although motility in mutant embryos is absent from the onset of activity on embryonic days (E) 3-4, muscle differentiation appears histologically normal up to about E8. After E8, however, previously separate muscles fuse or coalesce secondarily, and myotubes exhibit a progressive series of histological and ultrastructural degenerative changes, including disarrayed myofibrils, dilated sarcoplasmic vesicles, nuclear membrane blebbing, mitochondrial swelling, nuclear inclusions, and absence of junctional end feet. Mutant muscle cells do not develop beyond the myotube stage, and by E18-E20 most muscles have almost completely degenerated. Prior to their breakdown and degeneration, mutant muscles are innervated and synaptic contacts are established. In fact, quantitative analysis indicates that, prior to the onset of muscle degeneration, mutant muscles are hyperinnervated. There is increased branching of motoneuron axons and an increased number of synaptic contacts in the mutant muscle on E8. Naturally occurring cell death of limb-innervating motoneurons is also significantly reduced in cn/cn embryos. Mutant embryos have 30-40% more motoneurons in the brachial and lumbar spinal cord by the end of the normal period of cell death. Electrophysiological recordings (electromyographic and direct records form muscle nerves) failed to detect any differences in the activity of control vs. mutant embryos despite the absence of muscular contractile activity in the mutant embryos. The α- ryanodine receptor that is genetically abnormal in homozygote cn/cn embryos is not normally expressed in the spinal cord. Taken together, these data argue against the possibility that the mutant phenotype described here is caused by the perturbation of a central nervous system (CNS)-expressed α- ryanodine receptor. The hyperinnervation of skeletal muscle and the reduction of motoneuron death that are observed in cn/cn embryos also occur in genetically paralyzed mouse embryos and in pharmacologically paralyzed avian and rat embryos. Because a primary common feature in all three of these models is the absence of muscle activity, it seems likely that the peripheral excitation of muscle by motoneurons during normal development is a major factor in regulating retrograde muscle-derived for muscle-associated) signals that control motoneuron differentiation and survival.

Original languageEnglish (US)
Pages (from-to)353-372
Number of pages20
JournalJournal of Comparative Neurology
Volume381
Issue number3
DOIs
StatePublished - May 12 1997
Externally publishedYes

Keywords

  • cell death
  • chick embryo
  • muscle
  • neurons
  • spinal cord

ASJC Scopus subject areas

  • Neuroscience(all)

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    Oppenheim, R. W., Prevette, D., Houenou, L. J., Pinçon-Raymond, M., Dimitriadou, V., Donevan, A., O'Donovan, M., Wenner, P., Mckemy, D. D., & Allen, P. D. (1997). Neuromuscular development in the avian paralytic mutant crooked neck dwarf (cn/cn): Further evidence for the role of neuromuscular activity in motoneuron survival. Journal of Comparative Neurology, 381(3), 353-372. https://doi.org/10.1002/(SICI)1096-9861(19970512)381:3<353::AID-CNE7>3.0.CO;2-1