Coordinated changes in cellular behavior ensure the lifelong maintenance of the hippocampal stem cell population

Summary

Neural stem cell numbers fall rapidly in the hippocampus of juvenile mice but stabilize during adulthood, ensuring lifelong hippocampal neurogenesis. We show that this stabilization of stem cell numbers in young adults is the result of coordinated changes in stem cell behavior. Although proliferating neural stem cells in juveniles differentiate rapidly, they increasingly return to a resting state of shallow quiescence and progress through additional self-renewing divisions in adulthood. Single-cell transcriptomics, modeling, and label retention analyses indicate that resting cells have a higher activation rate and greater contribution to neurogenesis than dormant cells, which have not left quiescence. These changes in stem cell behavior result from a progressive reduction in expression of the pro-activation protein ASCL1 because of increased post-translational degradation. These cellular mechanisms help reconcile current contradictory models of hippocampal neural stem cell (NSC) dynamics and may contribute to the different rates of decline of hippocampal neurogenesis in mammalian species, including humans.

Graphical abstract

Highlights

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  More proliferating hippocampal stem cells return to shallow quiescence with age

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  Dormant stem cells enter deeper quiescence with age

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  These changes drive the transition from developmental to adult neurogenesis

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  Increasing degradation of ASCL1 protein by HUWE1 coordinates these changes

Abstract

Harris et al. show that multiple cellular changes work in concert during early life to preserve the hippocampal stem cell population throughout adulthood in mice. In particular, more proliferating stem cells return to quiescence instead of differentiating. The changes are coordinated by increasing degradation of the pro-activation factor ASCL1.