The proposed experiments are designed to examine the role of Pituitary Adenylate Cyclase Peptide (PACAP) in cerebral cortical development. Although originally identified as a hypothalamic factor that increased cAMP levels in pituitary via G-protein-coupled receptors, the 38-aa peptide, PACAP, has been demonstrated by RIA to be widely expressed and developmentally regulated in embryonic brain and peripheral sympathetic systems. In the previous funding period, investigators identified PACAP as an endogenous, autocrine/paracrine regulator of neurogenesis and survival of both central and peripheral neuronal populations. In cortex, PACAP promotes cell cycle withdrawal and differentiation of neurons, while in embryonic SCG cells it promotes proliferation, survival and differentiation. In this competing renewal application, the role and mechanisms of the PACAP ligand/receptor system will be defined in cortical precursors both in culture and in vivo. The central hypothesis to be tested is that the PACAP ligand/receptor system participates in the transition from proliferation to differentiation of cortical neurons, acting to inhibit proliferation by modulating mitogenic growth factor receptors and cell cycle signaling pathways. A 3 year funding period is proposed that will (a) define PACAP ligand/receptor expression during cortical development, (b) examine the effects of PACAP system activation in vivo, (c) examine PACAP regulation of cortical mitogen bFGF receptor expression and function in vitro, and (d) compare ontogenetic expression and PACAP modulation of cell cycle regulators, cyclin-dependent kinase (CDK2) and CDK inhibitor, p57.
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