The central goal of this program project is to elucidate integrative principles regulating brain development by defining sequential ontogenetic processes. We are pursuing the unifying concept that seemingly distinct developmental processes, including neuronal mitosis, aggregation, transmitter and receptor gene expression and trophic interactions with the formation of synaptic circuits are causally interrelated. During the past grant period we have begun to delineate the detailed causal mechanistic relationships among these processes. Our studies are now defining critical interactions among these phenomena. We are finding that a number of molecules integrate successive developmental processes through intercellular communication. We will employ multidisciplinary molecular genetic, biochemical, pharmacologic and morphologic approaches to study neuronal development in vivo and in culture. We plan to define a) regulation of peripheral and brain neuron mitosis by epigenetic and genomic factors, studying VIP (vasoactive intestinal peptide), second messenger kinase systems, and the protein Id, a negative regulator of helix-loop-helix DNA binding proteins; b) regulation of expression of the P75NGFR and P140trk product of the proto-oncogene trk, both of which bind NGF, by constructing fusion genes and examining expression in culture and in transgenic mice; c) mechanisms governing synaptic molecular architecture; d) mechanisms through which a fully-purified membrane factor regulates transmitter phenotypic expression and mitosis and e) regulation of the formation of brain circuits by individual members of the neurotrophin gene family. Our overall objective is to define molecular mechanistic relations among apparently diverse developmental processes. This information may define molecular loci where disease processes intervene, leading to abnormal brain development, birth defects and mental retardation.
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