Postdoctoral fellow The Chinese University of Hong Kong (CUHK) Hong Kong, Hong Kong
Abstract: 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 machinery enabling molecular changes for functional neuron generation from NSPCs remains elusive. The histone demethylase Kdm3a regulates genes that are involved in spermatogenesis, mammalian sex determination, lipid metabolism and cancer development. It was also found to orchestrate the expression levels of pluripotency genes, such as Tcl1 and Nanog, thereby establishing its vital role in maintaining the self-renewal capacity of embryonic stem cells. Despite these findings, the function of Kdm3a in the brain and particularly neurogenesis remains poorly understood. Employing reporter mice and knockout mice models will provide further insights into the specific contributions of Kdm3a to neurogenesis and potentially uncover therapeutic strategies for neurological disorders and injuries. 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. Intriguingly, Kdm3a regulates the Wnt/β-Catenin signaling pathway through both transcriptional and posttranslational mechanisms. Moreover, we identify that quercetin, a geroprotective small molecule, upregulates Kdm3a and promotes adult hippocampal neurogenesis following brain injury. 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 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.
Funding Source: Acknowledgement: This study is supported by GRF/UGC (14112223) and GRF/UGC (14116622).
