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

作者：Kin Pong U, Lin Gao, Huan Zhang, Zeyuan Ji, Jiacheng Lin, Shenyi Peng, Xiaohu Zhang, Shaolong Xue, Weifeng Qin, Lai Ling Tsang, Yonglun Kong, Yin Xia, Patrick Ming‐Kuen Tang, Tao Wang, Wayne Lee, Gang Li, Xiaohua Jiang · 发表于：Cell Death and Differentiation · 年份：2025 · DOI：10.1038/s41418-025-01470-2 · 被引用次数：7 · 研究领域：Neurogenesis and neuroplasticity mechanisms、Genetics and Neurodevelopmental Disorders、Epigenetics and DNA Methylation

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 ...