Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling.
Chd8 mediates cortical neurogenesis via transcriptional regulation of cell cycle and Wnt signaling.
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DOI：
10.1038/nn.4400
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发表时间：
2016-11
影响因子：
25
通讯作者：
Tsai LH
中科院分区：
文献类型：
--
作者：
Durak O;Gao F;Kaeser-Woo YJ;Rueda R;Martorell AJ;Nott A;Liu CY;Watson LA;Tsai LH
CHD8的新生突变与自闭症谱系障碍（ASD）密切相关，然而CHD8的基础生物学仍然知之甚少。在这里，我们报告说，Chd8敲低皮质发育过程中的缺陷神经祖细胞增殖和分化，最终表现在异常的神经元形态和行为在成年小鼠。转录组分析表明，虽然Chd8刺激细胞周期基因的转录，但它也通过调节PRC2复合物组分的表达来排除神经特异性基因的诱导。此外，Chd8的敲低破坏了Wnt信号传导的关键转导子的表达，并且增强Wnt信号传导挽救了由Chd8敲低引起的转录和行为缺陷。我们认为，这些作用的Chd8和动态的Chd8的表达在发展过程中帮助谈判神经祖细胞增殖和分化之间的平衡。总之，这些观察结果为Chd8的神经发育作用提供了新的见解。
De novo mutations in CHD8 are strongly associated with autism spectrum disorder (ASD), however the basic biology of CHD8 remains poor understood. Here we report that Chd8 knockdown during cortical development results in defective neural progenitor proliferation and differentiation that ultimately manifests in abnormal neuronal morphology and behaviors in adult mice. Transcriptome analysis revealed that while Chd8 stimulates the transcription of cell cycle genes, it also precludes the induction of neural specific genes by regulating the expression of PRC2 complex components. Furthermore, knockdown of Chd8 disrupts the expression of key transducers of Wnt signaling, and enhancing Wnt signaling rescues the transcriptional and behavioral deficits caused by Chd8 knockdown. We propose that these roles of Chd8 and the dynamics of Chd8 expression during development help negotiate the fine balance between neural progenitor proliferation and differentiation. Together, these observations provide new insights into the neurodevelopmental role of Chd8.