Molecular Control of Neural Stem Cell Quiescence in the Adult Zebrafish Telencephalon: Established Mechanisms and an Integrative Hypothesis

Abstract

The zebrafish telencephalon is an excellent model for adult neurogenesis under physiological and regenerative conditions, as many pathways regulating neural stem cell behavior are conserved with mammalian neurogenic niches. Resident radial glial cells (RGCs) serve as neural stem cells in the adult brain and are readily accessible in vivo, because forebrain eversion repositions the ventricular zone to the dorsal surface. Recent studies have revealed substantial heterogeneity among RGCs, including activation-primed cells and deeply quiescent states during homeostasis. Here, we first review the evidence that four mechanisms control quiescence in pallial RGCs: Notch3-mediated lateral inhibition, the neuronal bone morphogenetic protein (BMP)-Id1 axis, the nuclear receptor Nr2f1b, and the secreted factor Midkine-a. The evidence supporting them is unequal, and we state its level for each before asking whether they act together. Notch-mediated lateral inhibition and neuronal BMP-Id1 signaling converge on her4.1, the clearest documented interaction among them, whereas Nr2f1b establishes a deeper dormancy program that resists Notch and BMP inhibition and protects a reserve stem cell pool. Midkine-a is proposed to reinforce quiescence, pending functional validation. Finally, we propose as a hypothesis that these mechanisms act as partially redundant inputs whose relative contributions determine quiescence depth and vary along the antero-posterior axis of the pallium. Together, these findings reframe quiescence as a spectrum of actively maintained conditions rather than a passive default state. These mechanisms are conserved across vertebrates, with implications for understanding why mammalian neural stem cell pools decline with age and injury.