Pool-specific regulation of motor neuron survival by neurotrophic support

J Neurosci. 2011 Aug 3;31(31):11144-58. doi: 10.1523/JNEUROSCI.2198-11.2011.


The precise control of motor neuron (MN) death and survival following initial innervation of skeletal muscle targets is a key step in sculpting a functional motor system, but how this is regulated at the level of individual motor pools remains unclear. Hepatocyte growth factor (HGF) and its receptor Met play key developmental roles in both muscle and MNs. We generated mice (termed "Nes-Met") in which met is inactivated from midembryonic stages onward in the CNS only. Adult animals showed motor behavioral defects suggestive of impaired innervation of pectoral muscles. Correspondingly, in neonatal spinal cords of Nes-Met mutants, we observed death of a discrete population of pea3-expressing MNs at brachial levels. Axonal tracing using pea3 reporter mice revealed a novel target muscle of pea3-expressing MNs: the pectoralis minor muscle. In Nes-Met mice, the pectoralis minor pool initially innervated its target muscle, but required HGF/Met for survival, hence for proper maintenance of muscle innervation. In contrast, HGF/Met was dispensable for the survival of neighboring Met-expressing MN pools, despite its earlier functions for their specification and axon growth. Our results demonstrate the exquisite degree to which outcomes of signaling by receptor tyrosine kinases are regulated on a cell-by-cell basis. They also provide a model for one way in which the multiplicity of neurotrophic factors may allow for regulation of MN numbers in a pool-specific manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / physiology
  • Cell Survival / drug effects
  • Cell Survival / genetics
  • Cells, Cultured
  • Choline O-Acetyltransferase / metabolism
  • Core Binding Factor Alpha 2 Subunit / metabolism
  • Dose-Response Relationship, Drug
  • Embryo, Mammalian
  • Ganglia, Spinal / cytology
  • Gene Expression Regulation, Developmental / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / pharmacology*
  • Green Fluorescent Proteins / genetics
  • Hand Strength / physiology
  • Hepatocyte Growth Factor / genetics
  • Intermediate Filament Proteins / genetics
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Biological
  • Motor Activity / genetics
  • Motor Neurons / drug effects*
  • Motor Neurons / physiology*
  • Muscle Strength / genetics
  • Muscle, Skeletal / innervation
  • Muscle, Skeletal / metabolism
  • Mutation / genetics
  • Nerve Growth Factors / genetics
  • Nerve Growth Factors / pharmacology*
  • Nerve Tissue Proteins / genetics
  • Nestin
  • Proto-Oncogene Proteins c-ets / genetics
  • Proto-Oncogene Proteins c-met / genetics
  • Psychomotor Performance / physiology
  • Reaction Time
  • Rotarod Performance Test
  • Spinal Cord / cytology
  • Transcription Factors / genetics


  • Core Binding Factor Alpha 2 Subunit
  • Etv4 protein, mouse
  • Glial Cell Line-Derived Neurotrophic Factor
  • Intermediate Filament Proteins
  • Nerve Growth Factors
  • Nerve Tissue Proteins
  • Nes protein, mouse
  • Nestin
  • Proto-Oncogene Proteins c-ets
  • Runx1 protein, mouse
  • Transcription Factors
  • transcription factor PEA3
  • Green Fluorescent Proteins
  • Hepatocyte Growth Factor
  • Choline O-Acetyltransferase
  • Proto-Oncogene Proteins c-met