Coordination of Insulin-mediated Neural Stem Cell Proliferation and Stem Cell Niche Development

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Yuan, Xin, Biology - Graduate School of Arts and Sciences, University of Virginia
Siegrist, Sarah, Biology, University of Virginia

During development, early undifferentiated progenitors called stem cells generate functional tissue through cell growth and proliferation. Stem cells are either pluripotent or multipotent, capable of differentiating into a variety of cell types depending on their intrinsic properties and environmental cues. Precise regulation of stem cell proliferation, differentiation, and quiescence ensures the development of specialized daughter cells with spatial and temporal accuracy. This is essential for establishing functional organs and maintaining tissue homeostasis. One such population of undifferentiated progenitors are neural stem cells, which generate the neurons and glia in the brain responsible for life and survival. In Drosophila, neural stem cells, named neuroblasts (NBs), are maintained in a microenvironment termed the NB stem cell niche. NBs enter a dormancy state termed quiescence at the end of embryogenesis, and reactivate after larval feeding. Dietary nutrients promote stem cell proliferation within the niche through activation of the canonical Insulin/PI3K/AKT/TOR growth signaling pathway.
In this dissertation, I sought to uncover the cellular interactions between neural stem cells and their niche cells in response to dietary nutrients. I demonstrated that the cellular architecture of the Drosophila NB stem cell niche establishment requires dietary nutrients during early stages of development. We show that NBs in the central brain reside in a complex niche microenvironment consisting of cortex glia and cerebral trachea, the gas exchange organ that delivers oxygen to the brain. The establishment of this complex niche cytoarchitecture (cellular architecture) is nutrient and PI3-Kinase dependent. Additionally, we uncovered nutrient instructed coordination of growth between NBs, cortex glia, and trachea. NB reactivation from quiescence requires activated PI3-Kinase in both cortex glia and trachea. Conversely, glial membrane growth requires reactivated NBs. The nutrient-responsive growth of NBs and glia are mediated through Drosophila insulin-like peptide 2 (Dilp-2). In addition, through single Dilp mutant analysis of the 7 Dilps, we found that Dilp-1 and Dilp-7 are also required for NB reactivation in the central brain. The pancreatic β cell analogous organ, insulin producing neurons, are the cellular source of Dilp-2. Circulating Dilp-2 in the insect blood hemolymph, and Dilp-2 locally released onto the Dilp-recruiting neurons are both potential sources of insulin to reactivate quiescent NBs. These findings demonstrate that both NB exit from quiescence, and niche cytoarchitecture development are established through intercellular communication and nutrient signaling coordination. This work highlights the interplay of insulin-mediated neural stem cell proliferation, stem cell niche development and insulin-responsive neural circuitry essential for proper brain growth and development.

PHD (Doctor of Philosophy)
insulin, neural stem cells, stem cell niche, dietary nutrients, quiescence, Dilp-2
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