The central objective of this program project is to define integrative principles governing the diverse processes of brain development. We hypothesize that reciprocal neuron-neuron and neuron-glial-neuron interactions, mediated by a limited set of intercellular signals, coordinate seemingly unrelated developmental events. Specifically, (a) trophic factors, including the diffusible neurotrophin gene family members, b) growth (mitogenic) factors, including bFGF, c) membrane-bound, chemorepulsive, cellular labels of the Eph gene family, and d) conventional neurotransmitters working combinatorially, synchronize the developmental sequence. These molecular signals coordinate neuronal mitosis, selective survival, axogenesis, pathfinding, topographic projection and synaptic plasticity. The epigenetic molecular signals mediate and integrate neural activity, trophic and glial coordination of proliferation, selective survival, pathway formation and synaptic function. We will employ multidisciplinary molecular genetic, biochemical and morphologic approaches to study neuronal development in vivo and in culture. We plan to define a) neuroblasts, b) the role of peripheral bFGF in brain neurogenesis, c) the role of the p75 neurotrophin receptor in developmental cell death and survival, d) the role of Eph family ligands and receptors in brain topographic projection, e) trophic regulation of synaptic plasticity and 3) the role of astrocyte-neuron interactions in brain development.
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