Retinoic Acid Is Required for Neural Stem and Progenitor Cell Proliferation in the Adult Hippocampus

Neural stem and precursor cell (NSPC) proliferation in the rodent adult hippocampus is essential to maintain stem cell populations and produce new neurons. Retinoic acid (RA) signaling is implicated in regulation of adult hippocampal neurogenesis, but its exact role in control of NSPC behavior has not been examined. We show RA signaling in all hippocampal NSPC subtypes and that inhibition of RA synthesis or signaling significantly decreases NSPC proliferation via abrogation of cell-cycle kinetics and cell-cycle regulators. RA signaling controls NSPC proliferation through hypoxia inducible factor-1α (HIF1α), where stabilization of HIF1α concurrent with disruption of RA signaling can prevent NSPC defects. These studies demonstrate a cell-autonomous role for RA signaling in hippocampal NSPCs that substantially broadens RA's function beyond its well-described role in neuronal differentiation. [Display omitted] •Retinoic acid (RA) signaling in mouse hippocampal neural stem and progenitors (NSPCs)•Systemic reduction in RA synthesis impairs NSPC proliferation and neurogenesis•HIF1α acts downstream of RA to regulate NSPC S-phase re-entry and cell-cycle genes•RA signaling is required cell autonomously in NSPCs for normal proliferation In this article, Mishra and colleagues identify a critical role for retinoic acid (RA) signaling in adult hippocampal neural stem and progenitor cell (NSPC) proliferation via hypoxia inducible factor-1α. Using RA reporter mice and conditional disruption of RA signaling in adult NSPCs, the authors identify RA signaling in adult NSPCs and NSPC RA signaling is required for normal proliferative behavior.