KDM3A controls postnatal hippocampal neurogenesis via dual regulation of the Wnt/β-catenin signaling pathway

Hippocampal neurogenesis, the generation of new neurons in the dentate gyrus (DG) of mammalian hippocampus, is essential for cognitive and emotional processes. Despite advances in understanding the transcription factors and signaling pathways that regulate DG neurogenesis, the epigenetic mechanisms underlying the molecular changes necessary for granule neuron generation remain poorly understood. In this study, we investigate the role of the H3K9 demethylase KDM3A in postnatal neurogenesis in mouse DG. Using Kdm3a-tdTomato reporter mice, we demonstrate that KDM3A is predominantly expressed in neural stem/progenitor cells (NSPCs) during postnatal DG development. Conventional or conditional knockout (cKO) of Kdm3a in NSPCs hinders postnatal neurogenesis, compromising learning and memory abilities and impairing brain injury repair in mice. Loss of KDM3A in NSPCs suppresses proliferation and neuronal differentiation while promoting glial differentiation in vitro. KDM3A localizes both in the nucleus and cytoplasm of NSPCs and regulates the Wnt/β-catenin signaling pathway through dual mechanisms. Firstly, KDM3A modulates the transcription of Wnt targets and a set of neurogenesis-related genes through its histone demethylase activity. Secondly, in the cytoplasm, KDM3A interacts with casein kinase I alpha (CK1α), regulating its ubiquitination. Loss of KDM3A enhances CK1α stability, leading to increased phosphorylation and degradation of β-catenin. Finally, quercetin, a geroprotective small molecule, upregulates KDM3A protein expression and promotes adult hippocampal neurogenesis following brain injury. However, these effects are diminished in Kdm3a KO mice, indicating that quercetin primarily promotes hippocampal neurogenesis through the regulation of KDM3A. In conclusion, our study highlights KDM3A as a crucial regulator of postnatal hippocampal neurogenesis, influencing NSPC proliferation and differentiation via the Wnt/β-catenin signaling pathway. These findings have potential implications for the development of new therapeutic approaches for neurological disorders and injuries.