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Diet-Dependent Balance Between Autophagy and Proliferation Regulates Follicle Stem Cell Lifetime

出版	Drexel University, 2017
URL	http://books.google.com.hk/books?id=PtgttAEACAAJ&hl=&source=gbs_api

註釋Stem cells are essential for the overall wellbeing of an organism. Decline in stem cell number and function can lead to loss of tissue homeostasis and aging. Mechanisms essential for stem cell maintenance are not well understood. Diet-dependent signaling can regulate stem cell lifespan. Adult epithelial stem cells, called Follicle Stem Cells (FSCs) in Drosophila ovaries are one such stem cell population that switches from quiescent to proliferative states depending on nutrient availability. FSCs proliferate actively in the presence of food and switch to a quiescent state during low-nutrient availability. Recent work indicates that proliferation can extend FSC lifespan. We have previously shown that during lownutrient conditions, a transmembrane protein called Boi sequesters Hh ligand and limits FSC proliferation. Flies bearing a loss-of-function boi mutation (boi mutants) have increased Hh release and subsequent increased FSC proliferation. Despite increased FSC proliferation, we found that boi mutants become infertile rapidly relative to wild-type flies. Paradoxically, we also find that constitutive Hh signaling leads to FSC loss despite increased proliferation, suggesting that additional mechanisms contribute to stem cell lifespan. Using a genetic suppressor screen we determined that reducing the expression of core autophagy pathway genes restores the fertility of boi mutants. Moreover, boi and the Hh gof mutants have elevated levels of autophagy within FSCs. Autophagy is a conserved lysosome-dependent degradation pathway and plays important role in stem cell maintenance, differentiation, and quality control. Surprisingly, the effects of increased Hh activity on autophagy induction are separable from the Hh-mediated proliferation response in FSCs. We have identified that the primary Hh-pathway effector Smo is dispensable for autophagy signaling and that instead, signaling happens through Ptc, which negatively regulates most Hh-dependent processes. Together, these results support a model in which the Hh signaling pathway activates two responses, autophagy and proliferation, that contribute independently to regulation of FSC lifetime. A similar mechanism is observed in old, WT FSCs, suggesting that age-dependent shifting of the proliferation-autophagy balance decreases fertility in normal conditions. Strikingly, we find that this balance is coordinated via the Hh and Insulin signaling, with Insulin signaling inhibiting Hh-induced autophagy but not proliferation. Overall this thesis concludes that diet-dependent signaling controls the balance between autophagy and proliferation to maintain FSCs, providing a molecular mechanism that connects a balanced diet with reproductive lifespan.