Proceedings of the National Academy of Sciences of the United States of America | 2019
α2-Chimaerin is essential for neural stem cell homeostasis in mouse adult neurogenesis
Abstract
Significance Adult hippocampal neurogenesis, the lifelong generation of neurons in the dentate gyrus, is important for brain functioning, including learning, memory, and mood regulation. Its dysregulation is associated with cognitive decline and mood disorders. We discovered that the Rho GTPase-activating protein, α2-chimaerin, is essential for adult hippocampal neurogenesis, as it precisely regulates the transition of neural stem cells (NSCs) into intermediate progenitor cells (IPCs). Conditional knockout of α2-chimaerin in adult NSCs in the mouse hippocampus resulted in a loss of the Klotho-expressing NSC population and the premature differentiation of NSCs into IPCs, which impaired neuron production. These mice also exhibited compromised hippocampal synaptic plasticity and anxiety/depression-like behaviors. Thus, our findings revealed that α2-chimaerin is important in adult hippocampal neurogenesis. Adult hippocampal neurogenesis involves the lifelong generation of neurons. The process depends on the homeostasis of the production of neurons and maintenance of the adult neural stem cell (NSC) pool. Here, we report that α2-chimaerin, a Rho GTPase-activating protein, is essential for NSC homeostasis in adult hippocampal neurogenesis. Conditional deletion of α2-chimaerin in adult NSCs resulted in the premature differentiation of NSCs into intermediate progenitor cells (IPCs), which ultimately depleted the NSC pool and impaired neuron generation. Single-cell RNA sequencing and pseudotime analyses revealed that α2-chimaerin–conditional knockout (α2-CKO) mice lacked a unique NSC subpopulation, termed Klotho-expressing NSCs, during the transition of NSCs to IPCs. Furthermore, α2-CKO led to defects in hippocampal synaptic plasticity and anxiety/depression-like behaviors in mice. Our findings collectively demonstrate that α2-chimaerin plays an essential role in adult hippocampal NSC homeostasis to maintain proper brain function.