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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child Development Disorders, Pervasive / genetics*
  • Child Development Disorders, Pervasive / pathology*
  • Female
  • Forkhead Transcription Factors / metabolism*
  • Gene Expression Profiling
  • Humans
  • Induced Pluripotent Stem Cells
  • Male
  • Megalencephaly / genetics
  • Megalencephaly / pathology
  • Models, Biological
  • Nerve Tissue Proteins / metabolism*
  • Neurogenesis*
  • Neurons / cytology
  • Neurons / metabolism
  • Organoids / pathology
  • Telencephalon / embryology*
  • Telencephalon / pathology

Substances

  • FOXG1 protein, human
  • Forkhead Transcription Factors
  • Nerve Tissue Proteins

Associated data

  • GEO/GSE61476