Lysosome acidification integrates FOXO signaling and fatty acid metabolism to control adult hippocampal neural stem/progenitor cell proliferation

Neural stem/progenitor cells (NSPCs) in the hippocampal dentate gyrus generate neurons throughout life. Growth factors, transcriptional regulators, metabolism and cell homeostatic pathways all impact on NSPC proliferation. How such plethora of signals coordinately regulate the constant supply of sufficient numbers of neurons while avoiding premature proliferation-driven depletion of the NSPC pool is poorly understood. Here, we demonstrate that transcription factor forkhead box O (FOXO)-dependent lipid metabolism is essential to restrict NSPC proliferative activity. We show that FOXO regulated abundance of the monounsaturated fatty acid oleic acid controls vacuolar-ATPase (v-ATPase) proton pump assembly thereby regulating lysosome acidification and autolysosomal activity. Strikingly, promoting v-ATPase assembly corrected FOXO deficiency- and oleic acid-induced excessive NSPC proliferation. Our findings connect three central determinants of NSPC proliferation – FOXOs, lipid metabolism and lysosomal activity – thereby identifying a critical regulatory network capable of integrating growth factor signaling, cellular metabolism and cell homeostatic pathways to coordinate NSPC proliferation.