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

Elli Marinopoulou,Veronica Biga,Nitin Sabherwal,Anzy Miller,Jayni Desai,Antony D Adamson,Nancy Papalopulu

doi:10.1016/j.isci.2021.103198

Abstract

SummaryQuiescence 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.

Highlights

Quiescence is defined as a state of reversible growth arrest in which cells are not actively dividing but they retain the capacity to re-enter the cell cycle when exposed to the appropriate signals
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
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

Summary

Introduction

Quiescence is defined as a state of reversible growth arrest in which cells are not actively dividing but they retain the capacity to re-enter the cell cycle when exposed to the appropriate signals. Adult NSCs continuously generate new neurons in vivo, this does not seem to be a sufficient mechanism for regeneration and brain repair. It appears that the extracellular environment can restrict the activation of quiescent NSCs or their full differentiation potential upon activation (Magnusson and Frisen, 2016). Understanding how quiescent cells can be reactivated is the first key step to regeneration

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