TY - JOUR
T1 - FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders
AU - Mariani, Jessica
AU - Coppola, Gianfilippo
AU - Zhang, Ping
AU - Abyzov, Alexej
AU - Provini, Lauren
AU - Tomasini, Livia
AU - Amenduni, Mariangela
AU - Szekely, Anna
AU - Palejev, Dean
AU - Wilson, Michael
AU - Gerstein, Mark
AU - Grigorenko, Elena L.
AU - Chawarska, Katarzyna
AU - Pelphrey, Kevin A.
AU - Howe, James R.
AU - Vaccarino, Flora M.
N1 - Publisher Copyright:
© 2015 Elsevier Inc.
PY - 2015/7/18
Y1 - 2015/7/18
N2 - 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.
AB - 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.
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U2 - 10.1016/j.cell.2015.06.034
DO - 10.1016/j.cell.2015.06.034
M3 - Article
C2 - 26186191
AN - SCOPUS:84937212591
SN - 0092-8674
VL - 162
SP - 375
EP - 390
JO - Cell
JF - Cell
IS - 2
M1 - 8281
ER -