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

403 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Fingerprint Dive into the research topics of 'FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders'. Together they form a unique fingerprint.

  • Cite this

    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. (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