Quiescence is essential for the long-term maintenance of adult stem cells but how stem cells maintain quiescence is poorly understood. Here we show that neural stem cells in the adult mouse hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activated or quiescent states. We found that the inhibitor of DNA binding protein Id4 is enriched in quiescent neural stem cells and that elimination of Id4 results in abnormal accumulation of Ascl1 protein and premature stem cell activation. Accordingly, Id4 and other Id proteins promote elimination of Ascl1 protein in neural stem cell cultures. Id4 sequesters Ascl1 heterodimerisation partner E47, promoting Ascl1 protein degradation and stem cell quiescence. Our results highlight the importance of non-transcriptional mechanisms for the maintenance of neural stem cell quiescence and reveal a role for Id4 as a quiescence-inducing factor, in contrast with its role of promoting the proliferation of embryonic neural progenitors.
- Eskeatnaf Mulugeta
- Francois Guillemot
- Francois Guillemot
- Debbie LC van den Berg
- Emmanuelle Huillard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All procedures involving animals and their care were performed in accordance with the guidelines of the Francis Crick Institute, national guidelines and laws. This study was approved by the Animal Ethics Committee and by the UK Home Office (PPL PB04755CC). All surgery was performed under terminal pentobarbital anaesthesia, and every effort was made to minimise suffering.
- Gary L Westbrook, Oregon Health and Science University, United States
- Received: May 17, 2019
- Accepted: September 24, 2019
- Accepted Manuscript published: September 25, 2019 (version 1)
© 2019, Blomfield et al.
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