Return to quiescence of mouse neural stem cells by degradation of a proactivation protein

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Science  15 Jul 2016:
Vol. 353, Issue 6296, pp. 292-295
DOI: 10.1126/science.aaf4802

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Sending neural stem cells back to the garage

In the brain's hippocampus, which modulates memories and emotions, neural stem cells generate new neurons, even during adulthood. How many new neurons are generated, and when, follows from the balance between quiescence and proliferation in the pool of neural stem cells. Urbán et al. asked what signals send proliferating stem cells back into a quiescent state. They found that a key transcription factor that promotes cellular proliferation was degraded through the ubiquitinylation system. This molecular interaction regulated the return to a resting state, but one that was not quite as quiescent as the original state. Stem cells in this resting but primed state sustained the stem cell pool.

Science, this issue p. 292


Quiescence is essential for long-term maintenance of adult stem cells. Niche signals regulate the transit of stem cells from dormant to activated states. Here, we show that the E3-ubiquitin ligase Huwe1 (HECT, UBA, and WWE domain–containing 1) is required for proliferating stem cells of the adult mouse hippocampus to return to quiescence. Huwe1 destabilizes proactivation protein Ascl1 (achaete-scute family bHLH transcription factor 1) in proliferating hippocampal stem cells, which prevents accumulation of cyclin Ds and promotes the return to a resting state. When stem cells fail to return to quiescence, the proliferative stem cell pool becomes depleted. Thus, long-term maintenance of hippocampal neurogenesis depends on the return of stem cells to a transient quiescent state through the rapid degradation of a key proactivation factor.

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