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

Jessica Mariani, Gianfilippo Coppola, Ping Zhang, Alexej Abyzov, Lauren Provini, Livia Tomasini, Mariangela Amenduni, Anna Szekely, Dean Palejev, Michael Wilson, Mark Gerstein, Elena L. Grigorenko, Katarzyna Chawarska, Kevin A. Pelphrey, James R. Howe, Flora M. Vaccarino

Research output: Contribution to journalArticle

321 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Article number8281
Pages (from-to)375-390
Number of pages16
JournalCell
Volume162
Issue number2
DOIs
StatePublished - Jul 18 2015

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GABAergic Neurons
gamma-Aminobutyric Acid
Neurons
Glutamic Acid
Genes
Gene Regulatory Networks
Organoids
Brain
Cell proliferation
Stem cells
Cell culture
Transcription Factors
Induced Pluripotent Stem Cells
Cells
RNA
Brain Diseases
Human Development
RNA Interference
Transcriptome
Cell Cycle

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mariani, J., Coppola, G., Zhang, P., Abyzov, A., Provini, L., Tomasini, L., ... Vaccarino, F. M. (2015). FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. Cell, 162(2), 375-390. [8281]. https://doi.org/10.1016/j.cell.2015.06.034

FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. / Mariani, Jessica; Coppola, Gianfilippo; Zhang, Ping; Abyzov, Alexej; Provini, Lauren; Tomasini, Livia; Amenduni, Mariangela; Szekely, Anna; Palejev, Dean; Wilson, Michael; Gerstein, Mark; Grigorenko, Elena L.; Chawarska, Katarzyna; Pelphrey, Kevin A.; Howe, James R.; Vaccarino, Flora M.

In: Cell, Vol. 162, No. 2, 8281, 18.07.2015, p. 375-390.

Research output: Contribution to journalArticle

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 2015, 'FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders', Cell, vol. 162, no. 2, 8281, pp. 375-390. https://doi.org/10.1016/j.cell.2015.06.034
Mariani, Jessica ; Coppola, Gianfilippo ; Zhang, Ping ; Abyzov, Alexej ; Provini, Lauren ; Tomasini, Livia ; Amenduni, Mariangela ; Szekely, Anna ; Palejev, Dean ; Wilson, Michael ; Gerstein, Mark ; Grigorenko, Elena L. ; Chawarska, Katarzyna ; Pelphrey, Kevin A. ; Howe, James R. ; Vaccarino, Flora M. / FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders. In: Cell. 2015 ; Vol. 162, No. 2. pp. 375-390.
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