Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development.
Essential role of the nuclear isoform of RBFOX1, a candidate gene for autism spectrum disorders, in the brain development.
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DOI：
10.1038/srep30805
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发表时间：
2016-08-02
影响因子：
4.6
通讯作者：
Nagata K
中科院分区：
文献类型：
--
作者：
Hamada N;Ito H;Nishijo T;Iwamoto I;Morishita R;Tabata H;Momiyama T;Nagata K
编码mRNA剪接因子的RBFOX 1基因异常已被证明会导致自闭症谱系障碍和其他神经发育障碍。由于在神经元，RBFOX 1-isoform 1（iso 1），占主导地位的核亚型的病理生理意义，仍有待阐明，我们进行了全面的分析RbFOX 1-iso 1在小鼠皮质发育。Rbfox 1-iso 1在子宫内电穿孔敲低引起异常的神经元定位在皮质，这是由于受损的迁移。缺陷被发现发生在放射状迁移和终端易位，可能是由于受损的核分裂。轴突延伸和树突状分支也被抑制在体内Rbfox 1-iso 1缺陷的皮质神经元。此外，电生理学实验揭示了缺陷神经元的膜和突触特性的显著缺陷。通过体外分析进一步证实了异常形态;海马神经元中Rbfox 1-iso 1-konckdown导致初级轴突长度、树突总长度、棘密度和成熟棘数量减少。综上所述，本研究表明，Rbfox 1-iso 1在皮质发育过程中神经元迁移和突触网络形成中起着重要作用。这些关键过程中的缺陷可能会导致皮质神经元的结构和功能缺陷，从而导致RBFOX 1异常的神经发育障碍的病理生理学。
Gene abnormalities in RBFOX1, encoding an mRNA-splicing factor, have been shown to cause autism spectrum disorder and other neurodevelopmental disorders. Since pathophysiological significance of the dominant nuclear isoform in neurons, RBFOX1-isoform1 (iso1), remains to be elucidated, we performed comprehensive analyses of Rbfox1-iso1 during mouse corticogenesis. Knockdown of Rbfox1-iso1 by in utero electroporation caused abnormal neuronal positioning during corticogenesis, which was attributed to impaired migration. The defects were found to occur during radial migration and terminal translocation, perhaps due to impaired nucleokinesis. Axon extension and dendritic arborization were also suppressed in vivo in Rbfox1-iso1-deficient cortical neurons. In addition, electrophysiology experiments revealed significant defects in the membrane and synaptic properties of the deficient neurons. Aberrant morphology was further confirmed by in vitro analyses; Rbfox1-iso1-konckdown in hippocampal neurons resulted in the reduction of primary axon length, total length of dendrites, spine density and mature spine number. Taken together, this study shows that Rbfox1-iso1 plays an important role in neuronal migration and synapse network formation during corticogenesis. Defects in these critical processes may induce structural and functional defects in cortical neurons, and consequently contribute to the pathophysiology of neurodevelopmental disorders with RBFOX1 abnormalities.