Hes1 oscillation frequency correlates with activation of neural stem cells

Abstract

Quiescent neural stem cells (NSCs) are occasionally activated to undergo proliferation and subsequent neuronal differentiation. It was previously shown that the transcriptional repressor Hes1 is involved in both active and quiescent states of NSCs: when Hes1 expression oscillates, it periodically represses the proneural gene Ascl1, thereby driving Ascl1 oscillations, which regulate the active state, while sustained Hes1 expression continuously suppresses Ascl1, promoting quiescence. However, it remains to be analyzed how the transition from quiescent to active states of NSCs is controlled. Here, we found that overexpression of the active form of Notch1 significantly activates NSCs in both in-vitro and in-vivo conditions and that its levels are proportional to NSC activation. The active form of Notch1 induces a burst of Hes1 oscillations in quiescent NSCs, and the frequency of Hes1 oscillations, rather than the Hes1 peak levels, correlates with the efficiency of NSC activation. These results raised the possibility that bursting Hes1 oscillations could increase the chance of Ascl1 oscillations in quiescent NSCs, suggesting that Notch1-induced Hes1 oscillation is a cue for a transition from quiescent to active states of NSCs.