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Opposing Action of Hedgehog and Insulin Signaling Balances Proliferation and Autophagy to Determine Follicle Stem Cell Lifespan
Dev Cell. 2018 Sep 24;46(6) :720-734.e6
PMID: 30197240    PMCID: PMC6159899   
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Egg production declines with age in many species, a process linked with stem cell loss. Diet-dependent signaling has emerged as critical for stem cell maintenance during aging. Follicle stem cells (FSCs) in the Drosophila ovary are exquisitely responsive to diet-induced signals including Hedgehog (Hh) and insulin-IGF signaling (IIS), entering quiescence in the absence of nutrients and initiating proliferation rapidly upon feeding. Although highly proliferative FSCs generally exhibit an extended lifespan, we find that constitutive Hh signaling drives FSC loss and premature sterility despite high proliferative rates. This occurs due to Hh-mediated induction of autophagy in FSCs via a Ptc-dependent, Smo-independent mechanism. Hh-dependent autophagy increases during aging, triggering FSC loss and consequent reproductive arrest. IIS is necessary and sufficient to suppress Hh-induced autophagy, promoting a stable proliferative state. These results suggest that opposing action of diet-responsive IIS and Hh signals determine reproductive lifespan by modulating the proliferation-autophagy balance in FSCs during aging.
1878-1551 Singh, Tanu Lee, Eric H Hartman, Tiffiney R Ruiz-Whalen, Dara M O'Reilly, Alana M P30 CA006927/CA/NCI NIH HHS/United States R01 GM084947/GM/NIGMS NIH HHS/United States R01 HD065800/HD/NICHD NIH HHS/United States Journal Article United States Dev Cell. 2018 Sep 24;46(6):720-734.e6. doi: 10.1016/j.devcel.2018.08.008. Epub 2018 Sep 6.