Abstract: The mechanisms by which neural stem cells in the embryonic brain divide and generate daughter cells to build the cerebral cortex of the proper size and structure remain among the most compelling mysteries in biology and medicine. How these long, polarized cells split to produce two daughters with symmetric or asymmetric fates, while still maintaining the epithelial structure, remains unclear despite much progress. Proper mitosis (chromosome segregation) and cytokinesis (cytoplasm, organelle, and membrane segregation) of neural stem cells is essential for their proliferation and survival. Indeed, neural stem cells trigger apoptosis more easily than mature neurons or other dividing cell types. Yet how apoptosis is triggered and how it can be prevented are not understood. This proposal focuses on a specific genetic model of microcephaly in which neural stem cells appear to have difficulty with a late step of cell division (abscission), and trigger their own apoptosis. Surprisingly, the small brain size and survival of these mutant animals can be rescued by knockout of the tumor suppressor gene p53. The objective of this particular application is to elucidate how p53- dependent apoptosis is triggered in this model of microcephaly. The central hypothesis is that neural stem cells that cannot complete the last step of division of the daughters (abscission) trigger p53-dependent apoptosis. We will test this hypothesis through two Specific Aims: 1) determine the temporal and causal relationship between cytokinetic abscission defects and p53 activation in NSCs, and 2) elucidate this novel pathway of p53 activation. Our long-term goal is to elucidate how specific alterations in cell division mechanisms in neural stem cells during development can lead to variations in brain size and structure, malformations, or other disorders. The contributions of the proposed research are expected to be a novel pathway for p53 activation and apoptosis, and a more detailed understanding of how cell division defects lead to brain malformations. These contributions will be significant because they may uncover novel mechanisms that contribute to neural stem cell survival or death, and make predictions about possible treatments for specific types of microcephaly or other brain malformations resulting from excess apoptosis.