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

doi:10.1016/j.cell.2015.06.034

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

Quantitative Health Sciences

Research output: Contribution to journal › Article › peer-review

492 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 language	English (US)
Article number	8281
Pages (from-to)	375-390
Number of pages	16
Journal	Cell
Volume	162
Issue number	2
DOIs	https://doi.org/10.1016/j.cell.2015.06.034
State	Published - Jul 18 2015

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1016/j.cell.2015.06.034

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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

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

@article{6552bb2cacc54ae1a439665c9e933d0d,

title = "FOXG1-Dependent Dysregulation of GABA/Glutamate Neuron Differentiation in Autism Spectrum Disorders",

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.",

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

note = "Funding Information: We acknowledge support from the NIH and from the Harris Professorship fund. We thank Dr. Alexander Urban, Stanford University, for help in experimental design. We also acknowledge the support team of the Yale University Biomedical High Performance Computing Center (in particular, Robert Bjornson and Nicholas Carriero). We thank Anita Huttner for culturing fibrobasts, Ying Zhang for preparing the sequencing libraries, and Nathaniel Calixto and Anahita Amiri for help in iPSC maintenance and characterization. We thank Elizabeth Jonas for facilities and help with the preliminary patch clamp experiments on dissociated cultures. We acknowledge the following grant support: NIMH MH089176, MH087879 (F.M.V.), U54 MH066494 (Project 2, K.C.), and the State of Connecticut (F.M.V.) and the Foster-Davis Foundation Inc (G.C.) through the Brain and Behavior Research Foundation. This work was supported in part by grants from the Simons Foundation (SFARI #137055, F.M.V. and SFARI #206929 R10981, K.A.P.). We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base ( https://base.sfari.org ). We acknowledge the Yale Center for Clinical Investigation for clinical support in obtaining the biopsy specimens. We thank Dr. John Overton, the Yale Center for Genome Analysis and the Stanford Genomic Facility for advice in carrying out DNA and RNA sequencing. Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",

year = "2015",

month = jul,

day = "18",

doi = "10.1016/j.cell.2015.06.034",

language = "English (US)",

volume = "162",

pages = "375--390",

journal = "Cell",

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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 - Funding Information: We acknowledge support from the NIH and from the Harris Professorship fund. We thank Dr. Alexander Urban, Stanford University, for help in experimental design. We also acknowledge the support team of the Yale University Biomedical High Performance Computing Center (in particular, Robert Bjornson and Nicholas Carriero). We thank Anita Huttner for culturing fibrobasts, Ying Zhang for preparing the sequencing libraries, and Nathaniel Calixto and Anahita Amiri for help in iPSC maintenance and characterization. We thank Elizabeth Jonas for facilities and help with the preliminary patch clamp experiments on dissociated cultures. We acknowledge the following grant support: NIMH MH089176, MH087879 (F.M.V.), U54 MH066494 (Project 2, K.C.), and the State of Connecticut (F.M.V.) and the Foster-Davis Foundation Inc (G.C.) through the Brain and Behavior Research Foundation. This work was supported in part by grants from the Simons Foundation (SFARI #137055, F.M.V. and SFARI #206929 R10981, K.A.P.). We are grateful to all of the families at the participating Simons Simplex Collection (SSC) sites, as well as the principal investigators (A. Beaudet, R. Bernier, J. Constantino, E. Cook, E. Fombonne, D. Geschwind, R. Goin-Kochel, E. Hanson, D. Grice, A. Klin, D. Ledbetter, C. Lord, C. Martin, D. Martin, R. Maxim, J. Miles, O. Ousley, K. Pelphrey, B. Peterson, J. Piggot, C. Saulnier, M. State, W. Stone, J. Sutcliffe, C. Walsh, Z. Warren, E. Wijsman). We appreciate obtaining access to phenotypic data on SFARI Base ( https://base.sfari.org ). We acknowledge the Yale Center for Clinical Investigation for clinical support in obtaining the biopsy specimens. We thank Dr. John Overton, the Yale Center for Genome Analysis and the Stanford Genomic Facility for advice in carrying out DNA and RNA sequencing. 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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DO - 10.1016/j.cell.2015.06.034

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JF - Cell

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ER -

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

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