Sequential transcriptional programs underpin activation of hippocampal stem cells.

Adult neural stem cells exist on a continuum from deep to shallow quiescence that changes in response to injury or aging; however, the transcription factors controlling these stepwise transitions have not been identified. Single-cell transcriptomic analyses of mice with loss of function or increased levels of the essential activation factor Ascl1 reveal that Ascl1 promotes the activation of hippocampal neural stem cells by driving these cells out of deep quiescence, despite its low protein expression in this state. Subsequently, during the transition from deep to shallow quiescence, Ascl1 induces the expression of Mycn, which drives progression through shallow quiescent states toward a proliferating state. Together, these results define the required sequence of transcription factors during hippocampal neural stem cell activation and establish a combinatorial code for classifying these cells into deep and shallow quiescence.