mTORC1 supports progression toward activation competence in quiescent adult neural stem cells

Abstract

Neural stem cells (NSCs) sustain lifelong neurogenesis through the tight regulation of quiescence, self-renewal and differentiation. Quiescent NSCs (qNSCs) exist in distinct substates, ranging from deep to shallow quiescence, yet the mechanisms governing these transitions remain unclear. In long-term self-renewing NSCs of the adult zebrafish pallium, we show that mTORC1 activity is specifically enriched during a prolonged quiescence phase in which NSCs acquire activation competence. Functional perturbations, analyzed in situ and using single-cell RNA sequencing, reveal that mTORC1 regulates cell progression during this phase, concomitantly ensuring the correct tempo for NSC transition towards activation and the preservation of stemness. These findings challenge the classical view of mTORC1 as a simple regulator of proliferation and identify it as a key regulator of NSC quiescence heterogeneity and dynamics under physiological conditions. By coordinating stemness maintenance with activation competence, mTORC1 emerges as a central player balancing long-term NSC preservation with neurogenic output in the adult brain.