Developmental regulation of neural stem cell elimination

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DESCRIPTION (provided by applicant): The sheer number and diversity of cell types within the human brain is staggering. Understanding how this cell diversity is generated and organized in such a way that allows organisms to think and behave is of fundamental importance. All neurons within the brain are generated from neural stem cells, which are self-renewing multi-potent progenitors. Neural stem cells play a key role in regulating brain size and cell type diversity, since this population remains actively engaged in the cell cycle throughout development. While much effort is aimed towards identifying the molecular mechanisms regulating stem cell self-renewal, I have become fascinated by the converse. What are the molecular mechanisms that terminate neural stem cell divisions once development is complete, which is essential to ensure proper formation of brain circuitry and to inhibit tissue overgrowth and tumorigenesis. Beyond development, the answer to this question is of key importance for under-standing age- related cognitive declines, mood disorders, and limited regenerative capacity of adult brains. Here we use Drosophila as a model system in which to investigate the mechanisms that terminate the cell divisions of neural stem cells, known as neuroblasts in Drosophila. We find that a subset of neuroblasts, are eliminated during development by cell death. If death fails, then neuroblasts persist long term in the adult brain and continue generating new neurons. Flies provide an excellent model system for studying the mechanisms regulating neural stem cell elimination, because the brain is vastly less complex than mammals, there exists a range of sophisticated genetic tools for manipulating gene function, and many biological processes are evolutionarily conserved. The goal of this proposal is to identify extrinsic and intrinsic cues that regulate neural stem cell elimination using a genetic and cell biological approach. The first aim tests the hypothesis that ensheathing glia provide trophic support necessary for neuroblast survival. The second aim investigates whether neuroblasts enter autophagy, prior to their elimination via cell death, which may serve as a potent backup mechanism to ensure termination of neuroblast proliferation. In addition, we will carry out an unbiased forward genetic screen to identify genes required for neuroblast elimination. Finally, we propose to transition our work to a mammalian model system, which will provide greater insight into understanding human disease. One more long-term goal is to use Drosophila as a means for identifying genes required for neural stem cell elimination, and then test whether the mammalian orthologues share this common function. Under the mentorship of Dr. Iswar Hariharan, an expert in genetics and cancer biology, and under the guidance of Dr. Arturo Alvarez-Buylla, Dr. David Schaffer, and Dr. Andy Wurmser, all experts in mammalian neural stem cells and neurogenesis, the candidate will gain expertise in genetic screening, using mammalian model systems, and mammalian neural stem cell biology. This research and training plan will provide her with an excellent foundation with which to transition to an independent research position. PUBLIC HEALTH RELEVANCE: The goal of this project is to identify the molecular mechanisms that terminate cell divisions of neural stems during development. The results from the proposed research could provide insight into: 1) improving stem cell therapeutics by devising methods to promote stem cell survival. 2) determining whether aberrantly persisting neural stem cells cause brain tumors. 3) devising methods to replace neurons damaged by disease or injury. 4) a greater understanding of the basis of congenital brain defects, such as anencephaly or microcephaly.