FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting human brain development has precluded understanding of ASD pathophysiology. Here we use three-dimensional neural cultures (organoids) derived from i...
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Published in | Cell Vol. 162; no. 2; pp. 375 - 390 |
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Main Authors | , , , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Elsevier Inc
16.07.2015
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Subjects | |
Online Access | Get full text |
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Summary: | Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of re-enacting 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 toward GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.
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•iPSC-derived telencephalic organoids reflect human midfetal telencephalic development•Inhibitory neurons are overproduced in organoids from patients with idiopathic autism•Overproduction of inhibitory neurons is caused by increased FOXG1 gene expression
iPSC-derived brain organoids from autism patients reveal increased production of inhibitory neurons caused by increased FOXG1 gene expression, identifying this gene as a molecular signature of idiopathic ASD and a potential drug target. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Present address: Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905 These authors contributed equally to this work Present address: Bulgarian Academy of Sciences, Institute of Mathematics and Informatics, Sofia 1113, Bulgaria |
ISSN: | 0092-8674 1097-4172 |
DOI: | 10.1016/j.cell.2015.06.034 |