Ephrin-A3 promotes and maintains slow muscle fiber identity during postnatal development and reinnervation

J Cell Biol. 2015 Dec 7;211(5):1077-91. doi: 10.1083/jcb.201502036.


Each adult mammalian skeletal muscle has a unique complement of fast and slow myofibers, reflecting patterns established during development and reinforced via their innervation by fast and slow motor neurons. Existing data support a model of postnatal "matching" whereby predetermined myofiber type identity promotes pruning of inappropriate motor axons, but no molecular mechanism has yet been identified. We present evidence that fiber type-specific repulsive interactions inhibit innervation of slow myofibers by fast motor axons during both postnatal maturation of the neuromuscular junction and myofiber reinnervation after injury. The repulsive guidance ligand ephrin-A3 is expressed only on slow myofibers, whereas its candidate receptor, EphA8, localizes exclusively to fast motor endplates. Adult mice lacking ephrin-A3 have dramatically fewer slow myofibers in fast and mixed muscles, and misexpression of ephrin-A3 on fast myofibers followed by denervation/reinnervation promotes their respecification to a slow phenotype. We therefore conclude that Eph/ephrin interactions guide the fiber type specificity of neuromuscular interactions during development and adult life.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / physiology
  • Female
  • Gene Expression Regulation, Developmental
  • Immunohistochemistry
  • Ligands
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Microscopy, Fluorescence
  • Motor Neurons / physiology
  • Muscle, Skeletal / embryology
  • Muscle, Skeletal / growth & development*
  • Muscle, Skeletal / innervation*
  • Myofibrils / metabolism
  • Neurogenesis / physiology*
  • Neuromuscular Junction / physiology
  • Neuronal Plasticity
  • Phenotype
  • Receptor, EphA3 / metabolism*
  • Receptor, EphA8 / metabolism
  • Schwann Cells / metabolism
  • Sciatic Nerve / physiology


  • Ligands
  • Epha3 protein, mouse
  • Receptor, EphA3
  • Receptor, EphA8