Regulation of the response of injured spindle fibers by muscle-derived neurotrophin-3

Postnatally, NT-3 expression in skeletal muscle is localized to muscle spindles where it likely continues to regulate proprioceptive function. Transgenic mice overexpressing NT-3 in skeletal muscle under control of the myosin light chain promoter (mlc/NT-3 mice) have been used as a model to investigate the effects of muscle-derived NT-3 on proprioceptive DRG neurons following peripheral nerve injury. Studies assessing the consequences of nerve crush on retrograde transport, neuronal survival, axonal morphology, muscle spindle innervation, and locomotor performance all suggest that axonal degeneration of proprioceptive neurons is reduced following sciatic nerve injury in mice that overexpress NT-3 in muscle. Moreover, immunohistochemical analysis of the innervation of entire muscle spindles revealed that injured sensory and motor axons retract from and reinnervate intrafusal fibers in a strict hierarchical fashion that recapitulates the initial innervation of spindles during development. The hypothesis that NT-3 may delay the degeneration of spindle afferents was tested by treating wildtype mice with exogenous NT-3 prior to and following nerve injury. Intramuscular injections of human recombinant NT-3 (10mug) prior to nerve injury reproduced similar delays in axonal degeneration seen in mlc/NT-3 mice. Finally, we tested the hypothesis that chronic exposure to high levels of NT-3 primes proprioceptors to respond differently to peripheral nerve injury by culturing dissociated DRG neurons. After three days in culture, large DRG neurons from mlc/NT-3 mice extended longer neurites than neurons from wildtype mice. Together, these studies are providing insight into the mechanisms by which muscle-derived NT-3 affects the response injury of proprioceptive neurons to peripheral nerve injury. These results suggest that NT-3 may regulate gene expression that is involved in the response of large fibers to peripheral nerve injury.