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Cell. 2015 Jul 16;162(2):375-390. doi: 10.1016/j.cell.2015.06.034.

FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.

Author information

1
Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
2
Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
3
Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
4
Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA.
5
Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Program in Computation Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA.
6
Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA; Department of Neurobiology, Yale University, New Haven, CT 06520, USA. Electronic address: flora.vaccarino@yale.edu.

Abstract

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.

PMID:
26186191
PMCID:
PMC4519016
DOI:
10.1016/j.cell.2015.06.034
[Indexed for MEDLINE]
Free PMC Article
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