FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
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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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Transcriptome and gene network analysis revealed that ASD organoids display decreased cell cycle, synaptic overgrowth, and overproduction of GABAergic neurons.
“Transcriptome and gene network analysis revealed that ASD organoids display a decreased cell cycle, synaptic overgrowth, and overproduction of GABAergic neurons [46].”
From Utility of iPSC-Derived Cells for Disease Modeling, Drug Development, and Cell Therapy (2022) · cites this paper as [46]
The Results report increased synaptic puncta and evidence of GABAergic neuron overproduction in ASD-derived organoids. They report decreased cell-cycle length in ASD-derived iPSCs, with a similar trend in early neuronal progenitors, but no significant proliferation difference in more mature organoids; the claim blurs that developmental distinction. (LLM, conf=0.87)
Experimental — accuracy not yet measuredOrganoids are limited by phenotypic variability and low throughput.
“Although organoids have been used to investigate disease-associated genes9–11, they are limited by phenotypic variability and low throughput.”
From Single-cell brain organoid screening identifies developmental defects in autism (2023) · cites this paper as [10]
Forebrain organoids derived from four patients with severe idiopathic autism spectrum disorder showed dysregulation of FOXG1 expression, accelerated cell cycle progression and increased production of GABAergic neurons.
“Patient-derived organoids exhibited dysregulation of forkhead box G1 expression (an important gene for fore-brain development), accelerated cell cycle progression and increased production of GABAergic neurons.”
From The use of brain organoids to investigate neural development and disease (2017) · cites this paper as [83]
Brain organoids have been used to successfully model microcephaly, periventricular heterotopia, autism and other neurodevelopmental disorders that may have differential effects on various human brain regions.
“Brain organoids have been used to successfully model microcephaly2, periventricular heterotopia10, autism11 and other neurodevelopmental disorders12,13 that may have differential effects on the various human brain regions.”
From Inferring and perturbing cell fate regulomes in human brain organoids (2023) · cites this paper as [11]
A recent study with macrocephaly ASD also revealed high level of NPC proliferation in another four ASD individuals, which may be due to a deficiency in FOXG1-mediated pathways.
“In support of our data, a recent study with macrocephaly ASD also revealed high level of NPC proliferation in another four ASD individuals, which may be due to a deficiency in FOXG1-mediated pathways63.”
From Altered proliferation and networks in neural cells derived from idiopathic autistic individuals (2017) · cites this paper as [63]
ASD patient-derived iPSC studies find evidence of multiple fetal stage defects with commonality in excess proliferation and cell cycle acceleration defects, but heterogeneity in synaptogenesis effects; this points to fetal stage subtypes in ASD.
“Thus, ASD patient-derived iPSC studies find evidence of multiple fetal stage defects with commonality in excess proliferation and cell cycle acceleration defects, but heterogeneity in synaptogenesis effects. This points to fetal stage subtypes in ASD.”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [55]
Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition.
“Studies on CHD8 and iPS-derived ASD neurons indicate the dysregulation of proliferation and macrocephaly in ASD could be linked to the disruption of these signaling pathways and shortened G1/S transition[54, 55, 57, 94, 183, 192, 193].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [55]
ASD patient-derived iPSC models show that excess proliferation is a robust early fetal stage defect in every case examined.
“ASD patient-derived iPSC models show that excess proliferation is a robust early fetal stage defect in every case examined [54, 55].”
From The ASD Living Biology: from cell proliferation to clinical phenotype (2019) · cites this paper as [55]
In vitro iPSC studies have bridged molecular and cellular phenotypes of cell cycle timing during neural progenitor cell division to abnormal cortical development in ASD subjects with enlarged brains.
“Further strengthening this evidence, in vitro iPSC studies have bridged molecular and cellular phenotypes of cell cycle timing during neural progenitor cell division to abnormal cortical development in ASD subjects with enlarged brains.37, 102”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [102]
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- Authors
- Mariani, J., Coppola, G., Zhang, P., Abyzov, A., Provini, L., Tomasini, L., Amenduni, M., Szekely, A., Palejev, D., Wilson, M., Gerstein, M., Grigorenko, E. L., Chawarska, K., Pelphrey, K. A., Howe, J. R., & Vaccarino, F. M.
- Affiliations
- Yale University (US)
- Corresponding author
- Vaccarino, Flora M.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-07
- Volume
- 162
- Issue
- 2
- Pages
- 375-390
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4519016
- OpenAlex
- W1768523798
- Cited by
- 1,149
- References
- 54
- Citations by year
- 2026: 56 · 2025: 91 · 2024: 116 · 2023: 77 · 2022: 111 · 2021: 133 · 2020: 153 · 2019: 132 · 2018: 99 · 2017: 85 · 2016: 72 · 2015: 23
- FWCI
- 55.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Yale University
- Simons Foundation Autism Research Initiative
- National Institutes of Health
- National Institute of Mental Health (U54MH066494, MH089176, R01MH089176, MH087879, R33MH087879, R21MH087879)
- Yale Center for Clinical Investigation, Yale School of Medicine
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Keywords
- autism spectrum disorder, FOXG1, GABAergic neurons, glutamatergic neurons, neuronal differentiation, brain organoids, induced pluripotent stem cells, brain development, gene regulatory networks, symptom severity, gene expression profiling
- MeSH terms
- Child Development Disorders, Pervasive, Female, Humans, Male, Models, Biological, Nerve Tissue Proteins, Neurons, Organoids, Telencephalon, Gene Expression Profiling, Forkhead Transcription Factors, Neurogenesis, Induced Pluripotent Stem Cells, Megalencephaly
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