Dr. Snider proposes to examine the role of NT3 in guiding axons by creating focal sources of this neurotrophin and by disrupting endogenous gradients and focal sources of this same neurotrophin. Specifically, he will focus on peripheral and central projections of Ia afferent sensory neurons, a neuronal population known to be dependent on NT3 for survival and to express the major NT3 receptor trkC. Specific experiments to assess effects of NT3 on axonal growth and branching by creating sources of NT3 will: (1) express NT3 under the myogenenin promoter to assess effects on the projection to skeletal muscles (and presumed absence of effects on the central projection); (2) target NT3 to motoneurons and white matter, using the choline-o-acetyltransferase and myelin basic protein promoters, respectively. These sources are predicted to result in aberrant growth to preganglionic autonomic neurons and aberrant branching, respectively; (3) similar targeting of NT4 and BDNF to motoneurons using the ChAT promoter which is predicted to induce projections from other sensory neurons that do not normally innervate ventral spinal cord; (4) Crossing of the myogenin-NT3 mice with NT3 mutants which is predicted to spare Ia efferents but disrupt the postulated NT3 gradient in spinal cord, resulting in loss or aberrancy in the central projection; (5) Ablation of motoneurons with a ChAT-Diphtheria toxin construct which is predicted to reduce or eliminate the Ia projection to the central cord.
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