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J Cell Biol ; 211(5): 1077-91, 2015 Dec 07.
Article in English | MEDLINE | ID: mdl-26644518

ABSTRACT

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.


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