FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.
FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.
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DOI：
10.1016/j.cell.2015.06.034
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发表时间：
2015-07-16
期刊：
影响因子：
64.5
通讯作者：
Vaccarino FM
中科院分区：
文献类型：
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作者：
Mariani J;Coppola G;Zhang P;Abyzov A;Provini L;Tomasini L;Amenduni M;Szekely A;Palejev D;Wilson M;Gerstein M;Grigorenko EL;Chawarska K;Pelphrey KA;Howe JR;Vaccarino FM
自闭症谱系障碍（ASD）是一种大脑发育障碍。大多数病例缺乏明确的病因或遗传基础，并且难以重现人类大脑发育，因此无法理解ASD的病理生理学。在这里，我们使用来自诱导多能干细胞（iPSC）的三维神经培养物（类器官）来研究严重特发性ASD患者的神经发育改变。虽然没有已知的潜在的基因组突变可以确定，转录组和基因网络分析显示上调的基因参与细胞增殖，神经元分化和突触组装。ASD衍生的类器官表现出加速的细胞周期和GABA能抑制性神经元的过度产生。使用RNA干扰，我们表明，转录因子FOXG1的过度表达是负责GABA能神经元的过度生产。基因网络模块和FOXG1的表达改变与症状严重程度呈正相关。我们的数据表明，FOXG1引起的GABA能神经元命运的转变是ASD的发育前体。
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of reenacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from induced pluripotent stem cells (iPSCs) to investigate neurodevelopmental alterations in individuals with severe idiopathic ASD. While no known underlying genomic mutation could be identified, transcriptome and gene network analyses revealed upregulation of genes involved in cell proliferation, neuronal differentiation, and synaptic assembly. ASD-derived organoids exhibit an accelerated cell cycle and overproduction of GABAergic inhibitory neurons. Using RNA interference, we show that overexpression of the transcription factor FOXG1 is responsible for the overproduction of GABAergic neurons. Altered expression of gene network modules and FOXG1 are positively correlated with symptom severity. Our data suggest that a shift towards GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.