Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders.
Role of a circadian-relevant gene NR1D1 in brain development: possible involvement in the pathophysiology of autism spectrum disorders.
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DOI：
10.1038/srep43945
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发表时间：
2017-03-06
影响因子：
4.6
通讯作者：
Nagata KI
中科院分区：
文献类型：
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作者：
Goto M;Mizuno M;Matsumoto A;Yang Z;Jimbo EF;Tabata H;Yamagata T;Nagata KI
在我们之前的研究中，我们筛选了伴有和不伴有睡眠障碍的自闭症谱系障碍（ASD）患者的昼夜节律相关基因编码区的突变，并检测了包括NR1D1在内的几个时钟基因的突变。在这里，我们进一步筛查ASD患者的NR1D1突变，并确定了三个新的突变，包括一个新生杂合子c.1499 G > A（p.R500H）。然后，我们分析了Nr1d1在小鼠大脑皮层发育中的作用。急性敲除小鼠Nr1d1在子宫内电穿孔引起异常定位皮质神经元在皮质发生。野生型Nr1d1挽救了这种异常表型，但c.1499 G > A突变体不能挽救。延时成像显示Nr1d1缺陷皮层神经元的特征性异常迁移表型。当Nr1d1被敲除时，皮层神经元的轴突延伸和树突状乔木形成也被抑制，而脑室区的神经元祖细胞和干细胞的增殖不受影响。两者合计，Nr1d1被发现通过调节兴奋性神经元迁移和突触网络形成在皮质生成中发挥关键作用。这些结果表明，NR1D1的功能缺陷可能与ASD的病因和病理生理学。
In our previous study, we screened autism spectrum disorder (ASD) patients with and without sleep disorders for mutations in the coding regions of circadian-relevant genes, and detected mutations in several clock genes including NR1D1. Here, we further screened ASD patients for NR1D1 mutations and identified three novel mutations including a de novo heterozygous one c.1499 G > A (p.R500H). We then analyzed the role of Nr1d1 in the development of the cerebral cortex in mice. Acute knockdown of mouse Nr1d1 with in utero electroporation caused abnormal positioning of cortical neurons during corticogenesis. This aberrant phenotype was rescued by wild type Nr1d1, but not by the c.1499 G > A mutant. Time-lapse imaging revealed characteristic abnormal migration phenotypes in Nr1d1-deficient cortical neurons. When Nr1d1 was knocked down, axon extension and dendritic arbor formation of cortical neurons were also suppressed while proliferation of neuronal progenitors and stem cells at the ventricular zone was not affected. Taken together, Nr1d1 was found to play a pivotal role in corticogenesis via regulation of excitatory neuron migration and synaptic network formation. These results suggest that functional defects in NR1D1 may be related to ASD etiology and pathophysiology.