reproduced verbatim): The proposed research is a continuation of our ongoing studies of the development of the peripheral nervous system. These studies will employ a combined in vitro/in vivo approach to define the role of bone morphogenetic protein 4 (BMP4) in regulating the survival and differentiation of peripheral sympathetic, dorsal root ganglion, and cranial sensory ganglion neurons. The first set of studies will examine the proapoptotic and anti-proliferative effects of BMP4 and the role of the factor in inducing neuronal dependence on growth factors for survival in vitro. They will further examine the role of the factor in the induction and regulation of trkC expression and the facilitation of neuronal responses to neurotrophin 3. To define the actions of BMP4 in vivo we have constructed transgenic animals in which a keratin 14 promoter (K14) or a neuron specific enolase (NSE) promoter drives expression of either BMP4 or of the BMP inhibitor, noggin. This approach will allow examination of the effects of both loss of BMP function and gain of function in the developing peripheral nervous system. The NSE animals will be particularly useful for examining ganglion development during the period of time when neuroblasts stop dividing, begin to extend processes to targets, and switch the neurotrophin receptors they express. The Kl4 animals will be particularly useful for examining the effects of BMP4 on neurons that are innervating a target (skin). Specifically these studies will define trk expression and distribution, neuron numbers, and neuronal phenotype in the peripheral nervous system of the transgenic animals. They will further determine whether there are abnormalities in peripheral nerve function in these animals. In a broader sense these studies seek to define the role of intercellular communication in development and function of the nervous system. It is hoped that these studies will indicate biochemical loci where therapeutic intervention in disease processes may lead to a return to normal neuronal function.
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