The COMPASS Family Protein ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signaling
The COMPASS Family Protein ASH2L Mediates Corticogenesis via Transcriptional Regulation of Wnt Signaling
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DOI：
10.1016/j.celrep.2019.06.055
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发表时间：
2019-07-16
期刊：
影响因子：
8.8
通讯作者：
Peng, Xiaozhong
中科院分区：
文献类型：
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作者：
Li, Liang;Ruan, Xiangbin;Peng, Xiaozhong
在器官发生过程中，组蛋白甲基化是调节基因表达的关键，以维持干细胞并为其后代执行适当的分化程序。在这里，我们证明了COMPASS家族组蛋白甲基转移酶辅助因子ASH2L是维持神经前体细胞(NPC)以及新皮质发育过程中投射神经元的产生和定位所必需的。具体地说，NPC中Ash21的缺失会导致新皮质的畸形；突变的新皮质的神经元较少，其组成和板层位置也异常。此外，ASH2L缺失会损害H3K4的三甲基化和Wnt-β-catenin信号转导的特异性转录机制，通过干扰S期进入抑制细胞周期进程来抑制神经发生后期的NPC的增殖能力。ASH_2L消除后过表达β-连环蛋白可挽救细胞增殖缺陷。因此，我们的发现表明，在哺乳动物新皮质发育过程中，ASH2 L对于调节Wnt信号以维持神经前体细胞和产生完整的神经元是至关重要的。
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-beta-catenin signaling, inhibiting the proliferation ability of NPCs at late stages of neurogenesis by disrupting S phase entry to inhibit cell cycle progression. Overexpressing beta-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.