Sox5 controls the establishment of quiescence in neural stem cells during postnatal development

Abstract

Adult stem cell niches relays in the acquisition of a reversible state of quiescence to ensure long-lasting DNA integrity and cell expansion. Neural stem cells (NSCs) in the dentate gyrus (DG) enter quiescence before the adult hippocampal neurogenic niche is fully established. However, the mechanisms controlling NSC first quiescence entry and quiescence deepness are largely unknown. Using conditional mutant mouse during embryonic or postnatal stages, we have determined that transcription factor Sox5 is required to restrict first entry in quiescence. Moreover, we have found a critical window during the second postnatal week when NSCs build up a shallow quiescent state. Loss of Sox5 leads to an excess of NSCs in shallow quiescence, which are prone to activate, leading to a neurogenic burst in the adult DG and precocious depletion of the NSC pool. Mechanistically, Sox5 prevents an excess of BMP canonical signaling, a pathway that is required to maintain the correct levels of NSC quiescence during the second postnatal week. In conclusion, our results demonstrate that Sox5 is required to control the correct balance between shallow and deep quiescence during the first postnatal weeks of DG development, a balance which is essential for establishing long-lasting adult neurogenesis.