Kdm3a Controls Postnatal Hippocampal Neurogenesis via Dual Regulation of the Wnt/beta-Catenin Signaling Pathway

Hippocampal neurogenesis, the generation of new neurons in the dentate gyrus (DG) of mammalian hippocampus, plays a crucial role in cognitive and emotional processes. While significant progress has been made in identifying transcription factors and signaling pathways that regulate DG neurogenesis, the epigenetic mechanisms underlying the molecular changes necessary for functional neuron generation remain poorly understood. In this study, we investigate the role of the H3K9 demethylase Kdm3a in postnatal neurogenesis in the mouse DG. We demonstrate that KDM3A is predominantly expressed in neural stem/progenitor cells (NSPCs) during postnatal DG development using Kdm3a-tdTomato reporter mice. Global or conditional knockout (cKO) of Kdm3a in NSPCs hinders postnatal neurogenesis, leading to compromised learning and memory abilities, as well as impaired brain injury repair in mice. Loss of Kdm3a in NSPCs suppresses proliferation and neuronal differentiation while promoting glial differentiation in vitro. Interestingly, we find that KDM3A localizes both in the nucleus and cytoplasm of NSPCs and regulates the Wnt/beta-Catenin signaling pathway through dual mechanisms. Firstly, Kdm3a modulates the transcription and transactivation of beta-catenin through its histone demethylase activity. Secondly, in the cytoplasm, KDM3A interacts with casein kinase I alpha, regulating its ubiquitination. Loss of Kdm3a enhances casein kinase I alpha stability, leading to increased phosphorylation and degradation of beta-catenin. Moreover, we identify that quercetin, a geroprotective small molecule, upregulates Kdm3a and promotes adult hippocampal neurogenesis following brain injury. However, these effects are abolished in Kdm3a KO mice, indicating that quercetin primarily promotes hippocampal neurogenesis through the induction of Kdm3a. In conclusion, our study highlights Kdm3a as a crucial regulator of postnatal hippocampal neurogenesis, influencing NSPC proliferation and differentiation via the Wnt/beta-catenin signaling pathway. These findings provide important insights into the epigenetic mechanisms governing hippocampal neurogenesis, with potential implications for the development of new therapeutic approaches for neurological disorders and injuries.