The proposed research is a continuation of our ongoing studies of the mechanisms regulating development of the peripheral nervous system. The studies will focus on of the role of bone morphogenetic protein (BMP) signaling in the regulation of sensory and sympathetic neuron survival, in the acquistion of neuronal dependence upon neurotrophins for survival, and in the regulation of the density and phenotype of innervation of peripheral target structures. BMP signaling in target structures acts as a negative regulator of neuron survival and may be the signal that makes developing neurons dependent upon neurotrophins for their survival. BMP signaling also regulates the density and pattern of innervation of target tissues independent of effects of sensory neuron survival; BMP signaling reduces the density of innervation of target tissues in vivo whereas neurotrophin signaling enhances it. As part of our ongoing studies we have contstructed transgenic animals that overexpress an inhibitor of BMP signaling, noggin (K14-nog), or BMP4 itself (K14-BMP4) under the control of a keratin 14 promoter. The proposed studies will therefore utilize a combined in vivo / in vitro approach to define the mechanisms by which BMP signaling regulates peripheral neurons survival and target innervation, and the mechansims of underlying the acquisition of growth factor dependence by neurons. The first set of studies will define the receptors mediating BMP effects on neuronal survival and target innervation. The second set will examine the role of p75NGFR in BMP-mediated neuronal death and limitation of target innervation. The third set of studies will define the effects of BMP signaling on target innervation independent of effects on neuron survival by examining progeny of K14- BMP4 mice mated with mice with null mutation of bax. The final set of studies will define the role of BMP signaling in induction of neurotrophone dependence by examining progeny of K14-noggin mice mated with mice with null mutations of trkA or NGF. The long term goal of these studies is to define the mechanisms governing the formation of the peripheral nervous system, and to identify biochemical and molecular loci where therapeutic intervention may help to repair the developmentally disordered or damaged nervous system. In particular these studies may help to define new therapeutis strategies for treating sensory and autonomic neuropathies. ? ?
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