Mutations in CHD8, chromodomain helicase DNA-binding protein 8, are among the most replicated and common findings in genetic studies of autism spectrum disorder (ASD). The CHD8 protein is believed to act as a transcriptional regulator by remodeling chromatin structure and recruiting histone H1 to target genes. The mechanism by which deficiency of CHD8 causes ASD has not been fully elucidated. We examined the expression of CHD8 in human and mouse brains using both immunohistochemistry and RNA in situ hybridization. We performed in utero electroporation, neuronal culture, and biochemical analysis using RNAi to examine the functional consequences of CHD8 deficiency. We discovered that CHD8 is expressed highly in neurons and at low levels in glia cells in both humans and mice. Specifically, CHD8 is localized predominately in the nucleus of both MAP2 and parvalbumin-positive neurons. In the developing mouse brain, expression of Chd8 peaks from E16 to E18 and then decreases significantly at P14 to adulthood. Knockdown of Chd8 results in reduced axon and dendritic growth, disruption of axon projections to the contralateral cortex, and delayed neuronal migration at E18.5 which recovers by P3 and P7. Our findings indicate an important role for CHD8 in dendritic and axon development and neuronal migration and thus offer novel insights to further dissect the underlying molecular and circuit mechanisms of ASD caused by CHD8 deficiency.

中文翻译：

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自闭症相关的CHD8缺乏会损害轴突的发育和皮层神经元的迁移。

在自闭症谱系障碍（ASD）的遗传学研究中，CHD8（染色体域解旋酶DNA结合蛋白8）的突变是最复制和最常见的发现之一。据信，CHD8蛋白可通过重塑染色质结构并募集组蛋白H1来靶向基因，从而起转录调节剂的作用。CHD8缺乏导致ASD的机制尚未完全阐明。我们使用免疫组织化学和RNA原位杂交技术检查了人和小鼠大脑中CHD8的表达。我们进行了子宫内电穿孔，神经元培养和使用RNAi的生化分析，以检查CHD8缺乏症的功能后果。我们发现在人类和小鼠中，CHD8在神经元中高表达，在胶质细胞中低水平表达。具体来说，CHD8主要位于MAP2和小白蛋白阳性神经元的细胞核中。在发育中的小鼠大脑中，Chd8的表达从E16到E18达到峰值，然后在P14到成年期显着下降。击倒Chd8导致轴突和树突状生长减少，轴突向对侧皮质的投射受到破坏，以及E18.5处的神经元迁移延迟，P3和P7恢复了它。我们的发现表明CHD8在树突和轴突发育和神经元迁移中具有重要作用，因此提供了新的见解，以进一步剖析由CHD8缺乏引起的ASD的潜在分子和电路机制。击倒Chd8导致轴突和树突状生长减少，轴突向对侧皮质的投射受到破坏，以及E18.5处的神经元迁移延迟，P3和P7恢复了它。我们的发现表明CHD8在树突和轴突发育和神经元迁移中具有重要作用，因此提供了新的见解，以进一步剖析由CHD8缺乏引起的ASD的潜在分子和电路机制。击倒Chd8导致轴突和树突状生长减少，轴突向对侧皮质的投射受到破坏，以及E18.5处的神经元迁移延迟，P3和P7恢复了它。我们的发现表明CHD8在树突和轴突发育和神经元迁移中具有重要作用，因此提供了新的见解，以进一步剖析由CHD8缺乏引起的ASD的潜在分子和电路机制。