| Popis: |
A complex regulatory framework underlies the generation of newborn neurons in the adult mammalian brain, including the lifelong maintenance of neural stem cell (NSC) quiescence and instructing NSC entry to and exit from quiescence. Future therapies targeting endogenous repair of the aging or afflicted brain, including neurodegenerative pathologies, rely on present efforts to define and characterize the mechanisms underlying the regulation of adult NSC fate. In this dissertation, we demonstrate a requirement for the Rb/E2F axis in the regulation of the molecular program instructing adult NSC quiescence and activation, with a potential role in the impaired hippocampal function observed in Alzheimer's disease pathology. While Rb plays a role in the production and survival of hippocampal newborn neurons, we identify a collective requirement for Rb family proteins — pRb, p107 and p130 — as well as their targets, E2F family transcriptional activators E2F1 and E2F3, in the regulation of NSC quiescence and activation. We further demonstrate that this is mediated through pivotal factors REST and ASCL1, identified as direct molecular targets of the Rb/E2F axis, and that REST inactivation can partially rescue NSC depletion following Rb family loss. We finally demonstrate impaired NSC activation and a return to quiescence in the 3xTG-AD model of Alzheimer's disease, with altered expression of Rb/E2F genes observed within cell population-specific defects. Ultimately, this work addresses the key issue of how transcriptional signatures of quiescence and activation among adult NSCs are co- ordinated with cell cycle control, and demonstrates that Rb family proteins serve as master regulators of the molecular program instructing adult NSC exit from and re-entry into quiescence. |
