Quiescence of Adult Mammalian Neural Stem Cells: A Highly Regulated Rest.

Neural stem cells in the adult mammalian brain are the source of new neurons that contribute to complex sensory and cognitive functions. Most adult neural stem cells are maintained in a state of reversible cell cycle arrest, also called quiescence. Quiescent neural stem cells present a low rate of metabolic activity and a high sensitivity to their local signaling environment, and they can be activated by diverse physiological stimuli. The balance between stem cell quiescence and activity determines not only the rate of neurogenesis but also the long-term maintenance of the stem cell pool and the neurogenic capacity of the aging brain. In recent years, significant progress has been made in characterizing quiescent stem cells thanks to the introduction of new genomic and imaging techniques. We discuss in this review our current understanding of neural stem cell quiescence and its regulation by intrinsic and systemic factors.

Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells.

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 (NSCs) 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 NSCs 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 NSC cultures. Id4 sequesters Ascl1 heterodimerization partner E47, promoting Ascl1 protein degradation and stem cell quiescence. Our results highlight the importance of non-transcriptional mechanisms for the maintenance of NSC 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.