The central nervous system (CNS) has an astonishing diversity of neurons and glia. The diversity of cell types in the CNS has greatly increased throughout evolution and underlies our unique cognitive abilities. The diverse neurons and glia in the CNS are made from a relatively small pool of neural stem cells and progenitors. Understanding the developmental mechanisms that generate diverse cell types from neural progenitors will provide insight into the complexity of the mammalian CNS and guide stem cell based therapies for brain repair. Temporal patterning, during which individual neural progenitors change over time to make different neurons and a glia, is essential for the generation of neural diversity. However, the regulation of temporal patterning is poorly understood. Human outer subventricular zone (OSVZ) neural stem cells and Drosophila type II neural stem cells (called neuroblasts) both generate transit-amplifying intermediate neural progenitors (INPs). INPs undergo additional rounds of cell division to increase the number of neurons and glia generated in neural stem cell lineages. However, it is unknown whether INPs simply expand the numbers of a particular cell type or make diverse neural progeny. In this dissertation, I show that type II neuroblast lineages give rise to extraordinary neural diversity in the Drosophila adult brain and contribute diverse neurons to a major brain structure, the central complex. I find that INPs undergo temporal patterning to expand neural diversity in type II lineages. I show that INPs sequentially generate distinct neural subtypes; that INPs sequentially express Dichaete, Grainyhead, and Eyeless transcription factors; and that these transcription factors are required for the production of distinct neural subtypes. Moreover, I find that parental type II neuroblasts also sequentially express transcription factors and generate different neuronal/glial progeny over time, providing a second temporal identity axis. I conclude that neuroblast and INP temporal patterning axes act combinatorially to specify diverse neural cell types within adult central complex; OSVZ neural stem cells may use similar mechanisms to increase neural diversity in the human brain. This dissertation includes previously published co-authored material.

xi, 88 p. A print copy of this thesis is available through the UO Libraries. Search the library catalog for the location and call number. / Neuroblasts are the neural stem cells of the Drosophlia central nervous system. They are large cells that divide asymmetrically to renew another neuroblast and generate a smaller ganglion mother cell (gmc) that will divide once to produce two neurons. Combining genetic lineage tracing experiments with cell fate markers I isolated two separate neural stem cell populations with distinct locations and cellular behaviors in the larval brain. In my first chapter I introduce the central nervous system of Drosophila and in the next two sections of chapter I, I introduce the development of the optic lobe and central brain, two separate structures of the central nervous system. In my second chapter I characterize the lineage relationship of cells within the developing larval optic lobe and use cell fate markers to determine the identity of these cells. Next I examine the effect of spindle orientation on cell fate within epithelial cells of the optic lobe. In my third chapter I characterize another novel neural stem cell lineage in the larval brain containing GMCs with greater proliferation potential than a "canonical" GMC, and I term these, transit amplifying gmcs (TA-GMCs). Further I show that the parent neuroblast of these novel TA-GMCs does not asymmetrically segregate the fate determinant Prospero (Pros) thereby producing a GMC with greater proliferation potential. Finally I show that TA-GMCs do asymmetrically segregate the fate determinant Pros, divide slowly and give rise to up to 10 neurons which normal gmcs never do. In my fourth chapter I show preliminary work on the characterization of a mutation that causes excessive production of neuroblasts specifically in novel TA-GMC lineages. These findings reveal novel neural stem cell lineages, patterns of asymmetric cell division and patterns of neurogenesis that could aid in our understanding of neural stem cell biology and tumorogenesis. This dissertation includes both my previously published and my co-authored materials. / Adviser: Chris Doe

Vascular Endothelial Growth Factor (VEGF) is a highly conserved ligand that is involved in the regulation of angiogenesis and vasculogenesis, however, alternative roles of the ligand have been emerging. Organisms such as jellyfish and Drosophila contain VEGF homologs, yet they do not possess endothelial cells or a vascular system indicating that VEGF might have other primitive roles. In this current study we investigated how VEGF affects the post-natal development of the intestinal epithelial by either overexpressing VEGF or by reducing the bioavailability of VEGF with the overexpression of soluble VEGF receptor (sFLT-1) within the gastrointestinal tract. After three weeks of VEGF overexpression, mutant mice displayed an increase in villus height and proliferation in the transit-amplifying zone with the decrease of crypts per measured length and Lgr5 expression. On the other hand, sFLT-1 overexpressing mice had an increase in crypt depth with a decrease in villus height, proliferation in the transit-amplifying zone, crypts per measured length and reduced expression of Dll1 and Bmp4. Overall the availability of VEGF has the ability to alter the proliferation of progenitor cells in the crypt by either a direct or indirect signals. These studies reveal that by some means VEGF is altering the developing post-natal intestinal epithelium and proliferation. Largely, elucidating the interaction between VEGF and intestinal stem cells in intestinal development and differentiation may help to advance intestinal stem cell therapies in intestinal dysfunction or disease

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