Boucherie Cédric, Alkailani Maisa, Jossin Yves, Ruiz-Reig Nuria, Mahdi Asma, Aldaalis Arwa, Aittaleb Mohamed, Tissir Fadel
Université Catholique de Louvain, Institute of Neuroscience, Developmental Neurobiology, Avenue Mounier 73, Box B1.73.16, Brussels, Belgium.
Hamad Bin Khalifa University, College of Health and Life Sciences, Doha, Qatar.
J Adv Res. 2025 Jun;72:151-163. doi: 10.1016/j.jare.2024.07.012. Epub 2024 Jul 14.
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.
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.
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.
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.
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.
AUTS2基因与多种神经发育和精神疾病相关，并且被认为在获得人类特有的性状中发挥作用。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，而所报道的表型并不能如实地概括与AUTS2相关的人类疾病的全貌。
本研究的目的是评估AUTS2在神经祖细胞生物学、皮质神经发生和扩张中的作用；并了解其失调如何导致神经系统疾病。
我们筛选了文献，并对皮质发育过程中AUTS2的表达进行了时间点分析。我们利用子宫内电穿孔在体内急性调节发育中的大脑皮质中AUTS2的表达水平，并使用免疫荧光、细胞追踪和分选、转录组分析以及基因本体富集分析对皮质神经发生和形态发生进行了全面表征。
除了在有丝分裂后的神经元中表达外，我们还表明AUTS2在神经发生高峰期的神经祖细胞中也有表达。AUTS2的上调显著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444个基因与小鼠脑发育或功能无关。
该研究提供了证据表明AUTS2在生发区表达，并在神经祖细胞的命运决定中起关键作用，对皮质发生有影响。它还列出了AUTS2靶基因的完整清单，从而推进了AUTS2相关疾病的分子机制以及大脑皮质的进化扩张。
