The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
The State Key Laboratory of Medical Molecular Biology, Neuroscience Center, Medical Primates Research Center and Department of Biochemistry and Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine Peking Union Medical College, Beijing 100005, China.
Cell Rep. 2019 Jul 16;28(3):698-711.e5. doi: 10.1016/j.celrep.2019.06.055.
Histone methylation is essential for regulating gene expression during organogenesis to maintain stem cells and execute a proper differentiation program for their descendants. Here we show that the COMPASS family histone methyltransferase co-factor ASH2L is required for maintaining neural progenitor cells (NPCs) and the production and positioning of projection neurons during neocortex development. Specifically, loss of Ash2l in NPCs results in malformation of the neocortex; the mutant neocortex has fewer neurons, which are also abnormal in composition and laminar position. Moreover, ASH2L loss impairs trimethylation of H3K4 and the transcriptional machinery specific for Wnt-β-catenin signaling, inhibiting the proliferation ability of NPCs at late stages of neurogenesis by disrupting S phase entry to inhibit cell cycle progression. Overexpressing β-catenin after ASH2L elimination rescues the proliferation deficiency. Therefore, our findings demonstrate that ASH2L is crucial for modulating Wnt signaling to maintain NPCs and generate a full complement of neurons during mammalian neocortex development.
组蛋白甲基化对于器官发生过程中基因表达的调控至关重要，以维持干细胞并为其后代执行适当的分化程序。在这里，我们表明 COMPASS 家族组蛋白甲基转移酶共因子 ASH2L 对于维持神经祖细胞 (NPC) 以及在大脑皮层发育过程中投射神经元的产生和定位是必需的。具体来说，NPC 中 Ash2l 的缺失导致大脑皮层畸形；突变的大脑皮层神经元数量较少，其组成和层状位置也异常。此外，ASH2L 的缺失会损害 H3K4 的三甲基化以及特定于 Wnt-β-连环蛋白信号通路的转录机制，通过干扰 S 期进入来抑制细胞周期进程，从而在神经发生的晚期抑制 NPC 的增殖能力。在消除 ASH2L 后过表达 β-连环蛋白可挽救增殖缺陷。因此，我们的研究结果表明，ASH2L 对于调节 Wnt 信号通路以维持 NPC 并在哺乳动物大脑皮层发育过程中产生完整的神经元群体至关重要。
