title: FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders.
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.
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mariani
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Gianfilippo
authors.initials: G
authors.lastname: Coppola
authors.affiliation: Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.
authors.forename: Alexej
authors.initials: A
authors.lastname: Abyzov
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Provini
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Livia
authors.initials: L
authors.lastname: Tomasini
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Amenduni
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Department of Genetics, Yale University, New Haven, CT 06520, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Szekely
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Dean
authors.initials: D
authors.lastname: Palejev
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wilson
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Program in Computation Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06520, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Gerstein
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Elena L
authors.initials: EL
authors.lastname: Grigorenko
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Chawarska
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA.
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Pelphrey
authors.affiliation: Department of Pharmacology, Yale University, New Haven, CT 06520, USA.
authors.forename: James R
authors.initials: JR
authors.lastname: Howe
authors.affiliation: Program in Neurodevelopment and Regeneration, Yale University, New Haven, CT 06520, USA; Child Study Center, Yale University, New Haven, CT 06520, USA; Department of Neurobiology, Yale University, New Haven, CT 06520, USA. Electronic address: flora.vaccarino@yale.edu.
authors.forename: Flora M
authors.initials: FM
authors.lastname: Vaccarino
mesh_terms: D002659:Child Development Disorders, Pervasive / Q000235:genetics* / Q000473:pathology*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D008297:Male; D058627:Megalencephaly / Q000235:genetics / Q000473:pathology; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009940:Organoids / Q000473:pathology; D013687:Telencephalon / Q000196:embryology* / Q000473:pathology
chemical_list: C090173:FOXG1 protein, human; D051858:Forkhead Transcription Factors; D009419:Nerve Tissue Proteins