The purpose of the work outlined is to delineate novel developmental functions of neurotrophins (NTS) and glial-cell line derived neurotrophic factor (GDNF) family members using primary sensory neurons of the dorsal root ganglion (DRG) as a model system. In the prior funding period it was demonstrated that neurotrophin family members are selectively expressed in target fields of different classes of sensory neurons, that nociceptive and proprioceptive DRG neurons express different Trk receptor tyrosine kinases, and that nociceptors and proprioceptors are selectively eliminated in trkA and trkC null mutant mice, respectively. Studies are now proposed which will broaden our understanding of functions of neurotrophins in regulating sensory neuron development and delineate potential interactions with the recently discovered GDNF family of neuronal growth factors. Four questions will be addressed: I. Does NT-3 regulate the initial outgrowth and targeting or proprioceptive sensory axons? II. Do levels of NT-3 in developing muscle regulate numbers of spinal cord and brainstem neurons contacted by proprioceptive sensory axons? III. Do levels of NT-3 in spinal cord regulate terminal arborizations of proprioceptive sensory axons in motor pools? IV. Does GDNF act in concert with NT-3 to regulate proprioceptive neuron development? Enhanced understanding of biological actions of neurotrophins and GDNF is of particular importance now that clinical trials have begun assessing these molecules as treatments for peripheral neuropathies and motor neuron disease.
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