Journal article
FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
Cell, Vol.162(2), pp.375-390
07/16/2015
DOI: 10.1016/j.cell.2015.06.034
PMCID: PMC4519016
PMID: 26186191
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.
Details
- Title: Subtitle
- FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
- Creators
- Jessica Mariani - Yale UniversityGianfilippo Coppola - Yale UniversityPing Zhang - Yale UniversityAlexej Abyzov - Yale UniversityLauren Provini - Yale UniversityLivia Tomasini - Yale UniversityMariangela Amenduni - Yale UniversityAnna Szekely - Yale UniversityDean Palejev - Yale UniversityMichael Wilson - Yale UniversityMark Gerstein - Yale UniversityElena L. Grigorenko - Yale UniversityKatarzyna Chawarska - Yale UniversityKevin A. Pelphrey - Yale UniversityJames R. Howe - Yale UniversityFlora M. Vaccarino - Yale University
- Resource Type
- Journal article
- Publication Details
- Cell, Vol.162(2), pp.375-390
- DOI
- 10.1016/j.cell.2015.06.034
- PMID
- 26186191
- PMCID
- PMC4519016
- NLM abbreviation
- Cell
- ISSN
- 0092-8674
- eISSN
- 1097-4172
- Publisher
- Elsevier
- Number of pages
- 16
- Grant note
- U54MH066494 / NATIONAL INSTITUTE OF MENTAL HEALTH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Mental Health (NIMH) NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA Foster-Davis Foundation Inc. through the Brain and Behavior Research Foundation Harris Professorship fund 137055; 206929 R10981 / Simons Foundation (SFARI)
- Language
- English
- Date published
- 07/16/2015
- Academic Unit
- Surgery
- Record Identifier
- 9984322897902771
Metrics
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