Molecular regulation of neural stem cell quiescence by FoxO transcription factors

Neural stem cells (NSCs) are the origin of new neurons in the adult brain. The majority of NSCs reside in a state outside of the cell cycle known as quiescence, which helps to limit exhaustion of the NSC population. During aging, however, NSCs decline in number and grow increasingly quiescent, which both impair adult neurogenesis. Only finely tuned regulation of their cell cycle can ensure lifelong neurogenesis. We discovered that transcription factor FoxO6 is a novel regulator of NSC fates. In contrast to FoxO3, FoxO6 suppresses NSC quiescence during aging.
Interestingly, NSCs lacking FoxO6 exhibit a glioma-like molecular signature whereas FoxO6 expression is a prognostic factor for glioma patients. This indicates a role for FoxO6 in the oncogenic transformation of neural stem cells towards brain cancer stem cells. In addition, these FoxO6-deficient NSCs show strongly reduced expression of Hmgn2, an epigenetic regulator of the NSC lineage and which we identified to be a transcriptional target of FoxO3. An emerging role of NSC regulation is the circadian control over their cell cycle entry. We found that FoxO3 controls the cellular circadian clock in NSCs and is necessary for the correct timing of their proliferation in the hippocampus. Together, this shows that an interplay between FoxO3 and FoxO6 regulates NSC quiescence and is required for healthy aging.