Quiescence and stemness are two key features of adult stem cells, both of which are crucial for the long-term function of stem cells, but whether these features are linked or controlled by distinct molecular mechanisms is unclear. Here, Laure Bally-Cuif and co-workers investigate this issue by analysing neural stem cells (NSCs) in the adult zebrafish dorsal telencephalon (pallium). These cells, termed radial glial cells (RGs), are known to require Notch3 for maintaining quiescence, but the authors now reveal that Notch3 is also required for maintaining RG stemness; in the absence of Notch3, RGs undergo premature differentiation. Following on from this, the authors perform transcriptomic analyses of RGs from wild-type fish and notch3−/− mutants to identify Notch3 transcriptional targets. Combining this with transcriptomic analyses of quiescent RGs, activated RGs and non-RG neural progenitors, they report that distinct sets of Notch3 targets are associated with RG stemness versus quiescence. Finally, their detailed characterization of a stemness-specific target, Hey1, reveals that it is expressed in RGs in a Notch3-dependent manner and is required to maintain RG stemness, thereby preventing precocious differentiation, but is not needed for maintaining a quiescent state. Overall, these findings indicate that Notch3 has dual functions in vertebrate NSCs, regulating both quiescence and stemness via distinct sets of downstream effectors.
