Abstract
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Single-cell analysis has suggested a continuum of cell states as NSCs exit quiescence. Here we capture and characterize in vitro primed quiescent NSCs and identify LRIG1 as an important regulator. We show that BMP-4 signaling induces a dormant non-cycling quiescent state (d-qNSCs), whereas combined BMP-4/FGF-2 signaling induces a distinct primed quiescent state poised for cell cycle re-entry. Primed quiescent NSCs (p-qNSCs) are defined by high levels of LRIG1 and CD9, as well as an interferon response signature, and can efficiently engraft into the adult subventricular zone (SVZ) niche. Genetic disruption of Lrig1 in vivo within the SVZ NSCs leads an enhanced proliferation. Mechanistically, LRIG1 primes quiescent NSCs for cell cycle re-entry and EGFR responsiveness by enabling EGFR protein levels to increase but limiting signaling activation. LRIG1 is therefore an important functional regulator of NSC exit from quiescence.
Highlights
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation
subventricular zone (SVZ) NSCs are responsible for the production of neuroblasts that migrate along the rostral migratory stream (RMS), destined for terminal neuronal differentiation in the olfactory bulb (OB)[4]
The in vitro models we developed here have helped to explore these distinct quiescent states and identify LRIG1 as an important regulator of the primed quiescent NSC state
Summary
Adult neural stem cells (NSCs) must tightly regulate quiescence and proliferation. Generation of new cells that are needed for tissue turnover and repair requires tight regulation as cells transit from dormant or slow-cycling states, into rapid proliferation. NSC quiescence is controlled in vivo by a complex repertoire of signals provided by the SVZ niche[10] These include local cell-cell interactions, secreted factors from the blood or cerebrospinal fluid, as well as longer range signals from neuronal inputs or factors secreted from the choroid plexus[11,12,13]. The BMP downstream effector, Id1 is a marker of quiescent NSCs in vivo[19] This local niche regulates the cell cycle state[14,18,20,21,22]
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