HES1 protein oscillations are necessary for neural stem cells to exit from quiescence

Quiescence is a dynamic process of reversible cell-cycle arrest. High-level persistent
expression of the HES1 transcriptional repressor, which oscillates with an ultradian periodicity
in proliferative neural stem cells (NSCs), is thought to mediate quiescence. However, it is not
known whether this is due to a change in levels or dynamics. Here, we induce quiescence in
embryonic NSCs with BMP4, which does not increase HES1 level, and we find that HES1
continues to oscillate. To assess the role of HES1 dynamics, we express persistent HES1 under
a moderate-strength promoter, which overrides the endogenous oscillations while maintaining
the total HES1 level within physiological range. We find that persistent HES1 does not affect
proliferation or entry into quiescence, however, exit from quiescence is impeded. Thus,
oscillatory expression of HES1 is specifically required for NSCs to exit quiescence, a finding
of potential importance for controlling reactivation of stem cells in tissue regeneration and
cancer.