The central objective of this program project is to define integrative principles governing the diverse processes of brain development and plasticity. We hypothesize that reciprocal stem cell differentiation, and neuron-neuron and neuron-Glial-neuron interactions, mediated by a limited set of inter- and intra-cellular signals, coordinate gene expression and seemingly unrelated developmental events. Moreover, specific genes, such as Rab3A, regulate trophin-induced synaptic plasticity. Specifically: a) trophic factors, including the diffusible neurotrophin gene family members, b) growth (mitogenic) factors, including bFGF and IGF-1, mediated by cyclins, CDKs and CKIs, c) membrane-bound cellular labels of the Eph gene family, d) neurotransmitters and the hormone, estradiol and e) the newly discovered intracellular trophin transduction molecule ARMS, working combinatorially, synchronize the developmental sequence. These molecular signals coordinate stem cell commitment and differentiation, neuronal mitosis, selective survival, axonal pathfinding, topographic projection, synaptogenesis and synaptic plasticity. We will employ multidisciplinary molecular genetic, transcriptional, biochemical and morphologic approaches at the population and single cell levels to study development and plasticity in vivo and in culture. We plan to define a) epigenetic regulation of stem cell and precursor mitosis and differentiation, b) the roles of bFGF and IGF-1 in cortical development, c) the role(s) of ARMS in mediating p75 and trk neurotrophin receptor actions in development and plasticity, d) the actions of Eph ligands and receptors in axon defasciculation and synaptogenesis in targets, e) trophic regulation of genes at the single cell level regulating synaptic plasticity and synaptogenesis, and f) the role of astrocyte-neuron interactions in brain development.