Auts2 可增强神经发生,促进大脑皮层的扩展。

Cédric Boucherie, Maisa Alkailani, Yves Jossin, Nuria Ruiz-Reig, Asma Mahdi, Arwa Aldaalis, Mohamed Aittaleb, Fadel Tissir
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引用次数: 0

摘要

简介AUTS2基因与多种神经发育和精神疾病有关,并被认为在获得人类特异性特征方面发挥作用。对 Auts2 基因敲除小鼠的功能分析主要集中在有丝分裂后的神经元上,所报道的表型并不能忠实地再现 AUTS2 相关人类疾病的整个谱系:本研究的目的是评估 AUTS2 在神经祖细胞生物学、皮质神经发生和扩增中的作用,并了解其失调如何导致神经系统疾病:我们对文献进行了筛选,并对大脑皮层发育过程中 AUTS2 的表达进行了时点分析。我们利用宫内电穿孔技术急性调控了 AUTS2 在体内大脑皮层发育过程中的表达水平,并通过免疫荧光、细胞追踪和分选、转录组图谱分析以及基因本体富集分析等方法全面描述了大脑皮层神经发生和形态发生的特征:结果:除了在有丝分裂后神经元中表达外,我们还发现 AUTS2 还在神经发生高峰期的神经祖细胞中表达。AUTS2的上调极大地改变了皮质祖细胞的分化程序和命运决定。值得注意的是,它增加了基底祖细胞和神经元的数量,并改变了数百个基因的表达,其中有 444 个基因与小鼠大脑发育或功能无关:结论:这项研究提供了证据,表明 AUTS2 在生殖区表达,并在神经祖细胞的命运决定中发挥关键作用,对皮质的形成产生影响。该研究还提供了全面的 AUTS2 靶基因列表,从而推进了 AUTS2 相关疾病的分子机制以及大脑皮层的进化扩展。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Auts2 enhances neurogenesis and promotes expansion of the cerebral cortex.

Introduction: The AUTS2 gene is associated with various neurodevelopmental and psychiatric disorders and has been suggested to play a role in acquiring human-specific traits. Functional analyses of Auts2 knockout mice have focused on postmitotic neurons, and the reported phenotypes do not faithfully recapitulate the whole spectrum of AUTS2-related human diseases.

Objective: The objective of the study is to assess the role of AUTS2 in the biology of neural progenitor cells, cortical neurogenesis and expansion; and understand how its deregulation leads to neurological disorders.

Methods: We screened the literature and conducted a time point analysis of AUTS2 expression during cortical development. We used in utero electroporation to acutely modulate the expression level of AUTS2 in the developing cerebral cortex in vivo, and thoroughly characterized cortical neurogenesis and morphogenesis using immunofluorescence, cell tracing and sorting, transcriptomic profiling, and gene ontology enrichment analyses.

Results: In addition to its expression in postmitotic neurons, we showed that AUTS2 is also expressed in neural progenitor cells at the peak of neurogenesis. Upregulation of AUTS2 dramatically altered the differentiation program and fate determination of cortical progenitors. Notably, it increased the number of basal progenitors and neurons and changed the expression of hundreds of genes, among which 444 have not been implicated in mouse brain development or function.

Conclusion: The study provides evidence that AUTS2 is expressed in germinal zones and plays a key role in fate decision of neural progenitor cells with impact on corticogenesis. It also presents comprehensive lists of AUTS2 target genes thus advancing the molecular mechanisms underlying AUTS2-associated diseases and the evolutionary expansion of the cerebral cortex.

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