FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders

By J. Mariani, Gianfilippo Coppola, Ping Zhang, Alexej Abyzov, Lauren E Provini, Livia Tomasini, M. Amenduni, A. Szekely, D. Palejev, Michael Wilson and 6 more. Cell, 2015

1,017 citations recorded by the source corpus.

SUMMARY Autism spectrum disorder (ASD) is a disorder of brain development. Most cases lack a clear etiology or genetic basis, and the difficulty of reenacting 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 towards GABAergic neuron fate caused by FOXG1 is a developmental precursor of ASD.

Subfields: Cellular and Molecular Neuroscience, Cognitive Neuroscience, Genetics

View Paper: https://www.semanticscholar.org/paper/5478f01696b9ef1abbb8efd5bca6e9bb252fe5f1

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Citations in the corpus

Midbrain-like organoids from human pluripotent stem cells contain functional dopaminergic and neuromelanin producing neurons (2016, background): “These limitations have prompted the development of 3D organoid models that mimic the organization and function of brain parts using hPSCs (Lancaster et al., 2013; Mariani et al., 2015; Muguruma et al., 2015; Paşca et al., 2015; Qian et al., 2016).”
Zika Virus Depletes Neural Progenitors in Human Cerebral Organoids through Activation of the Innate Immune Receptor TLR3 (2016, positive): “…and can recapitulate forebrain, midbrain, and hindbrain regions with functional electrophysiological properties to probe the mechanisms of neurodevelopment, autism, and microcephaly (Camp et al., 2015; Eiraku et al., 2008; Lancaster et al., 2013; Mariani et al., 2015; Nowakowski et al., 2016).”
The Cellular and Molecular Landscapes of the Developing Human Central Nervous System (2016, positive): “…in a wide array of neurological and psychiatric disorders (Brennand et al., 2011; Hu et al., 2014; Jeste and Geschwind, 2015; Lancaster et al., 2013; Mariani et al., 2015; Marin-Valencia et al., 2014; Stiles and Jernigan, 2010; Tau and Peterson, 2010; Tebbenkamp et al., 2014; Wen et al., 2014).”
Brain Region-specific Organoids using Mini-bioreactors for Modeling ZIKV Exposure (2016, positive): “Several pioneering studies showed that cerebral organoid systems offer improved growth conditions for 3D tissue, leading to a more representative model of the developing human brain (Danjo et al., 2011; Kadoshima et al., 2013; Lancaster et al., 2013; Mariani et al., 2015; Pasca et al., 2015).”
Advancing the understanding of autism disease mechanisms through genetics (2016, neutral): “Furthermore, an E/I imbalance may arise not only from changes in synaptic physiology but also from altered cell fate that can lead to abnormal proportions of inhibitory and excitatory cells, as evidenced by recent findings in human in vitro models 103 ( Table 2 and Fig.”
Human cerebral organoids recapitulate gene expression programs of fetal neocortex development (2015, background): “Bulk transcriptome analysis has provided a genome-wide perspective of the gene expression landscape in whole organoids (12).”