Heterogeneously expressed fezf2 patterns gradient notch activity in balancing the quiescence, proliferation, and differentiation of adult neural stem cells

Abstract

Balancing quiescence, self-renewal, and differentiation in adult stem cells is critical for tissue homeostasis. The underlying mechanisms, however, remain incompletely understood. Here we identify Fezf2 as a novel regulator of fate balance in adult zebrafish dorsal telence-phalic neural stem cells (NSCs). Transgenic reporters show intermingled fezf2-GFPhi quiescent and fezf2-GFPlo proliferative NSCs. Constitutive or conditional impairment of fezf2 activity demonstrates its requirement for maintaining quiescence. Analyses of genetic chimeras reveal a dose-dependent role offezf2 in NSC activation, suggesting that the difference in fezf2 levels directionally biases fate. Single NSCprofiling coupled with genetic analysis further uncovers afezf2-dependent gradient Notch activity that is high in quiescent and low in proliferative NSCs. Finally,fezf2-GFPhi quiescent andfezf2-GFPlo proliferative NSCs are observed in postnatal mouse hippocampus, suggesting possible evolutionary conservation. Our results support a model in which fezf2 heterogeneity patterns gradient Notch activity among neighbors that is critical to balance NSC fate.