Anniversary Lecture

Sleep well: the regulation of neural stem cell quiescence

Isabel Fariñas

Quiescence is a durable yet reversible arrest of the cell cycle that represents an adaptive feature of most adult stem cell populations. In the brain, this state protects adult neural stem cells from stress while supporting lifelong neurogenesis. However, the capacity to adopt a quiescent or slow-cycling state is also a defining characteristic of brain cancer stem cells, where it promotes malignancy. Although multiple signaling pathways are known to initiate quiescence in adult neural stem cells, the mechanisms that actively preserve this state over long periods remain incompletely understood. The subependymal zone lining the lateral ventricles of the mouse brain constitutes the largest adult neurogenic niche, in which neural stem cells reversibly transition between quiescent and activated states to continuously generate new neurons for adaptive olfactory circuits. We found that entry into quiescence is accompanied by the deposition of specific extracellular matrix components, and that adhesion to this matrix, produced in response to pro-quiescent cues, is sufficient to induce a quiescent-like state in proliferative neural stem cells. This process requires RhoA-associated kinase (ROCK) activity and transcriptional activation by yes-associated protein (YAP). Together, our results provide functional evidence that quiescent neural stem cells actively remodel the extracellular matrix of their niche. Moreover, while YAP-mediated mechanotransduction has always been linked to cell proliferation, tissue regeneration, and stemness across many tissues, our study uncovers an unexpected role for YAP in the active maintenance of dormancy in a physiological adult stem cell population.