This proposal's long standing objective is understanding the cellular events and molecular mechanisms that govern development of the mammalian central nervous system. The present proposal focuses on the issue of regulation of cell number allocated to the building of the cerebral cortex. Cell production in the embryonic ventricular zone (VZ) depends on rate of cell birth, fraction of cells leaving the cycle, extent of programmed cell death (PCD) and potential for postdevelopmental neurogenesis. New technology allows the analysis of the fundamental cellular and molecular mechanisms controlling cell number in mammals including primates. Three interrelated specific aims are proposed: !) examination of whether the members of Notch and Delta/Jagged gene families modulate proliferation and cell-fate restriction of VZ progenitors in the mouse and monkey cerebrum, and determine their involvement in regulating number and ratio of neurons with distinct cellular and laminar fates: 2) examine the role of PCD in controlling cell number in the VZ and cortical architecture by manipulating apoptosis through the use of transgenic mice that exhibit decreased apoptosis (CPP32 -/-) alone or in combination with mutants defective for the protector gene (Bcl-xl). Mechanisms of resistance of CPP32 deficient neurons to induced PCD will be studied in vitro and in heterochronic transplants; 3) examine whether or not postdevelopmental neurogenesis occurs in the adult monkey hippocampal formation with the most sensitive techniques and whether or not proliferation can be induced by agents that promote proliferation or environmental factors. The proposal brings knowledge derived from genes identified in invertebrates and from genetically engineered mice to the study of primate neurobiology with the goal of increasing our knowledge of normal and pathological cortical development.
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