Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons

Scientific Reports
Brooke A DeRosaDerek M Dykxhoorn

Abstract

Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.

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Citations

Aug 10, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Guang Yang, Alex Shcheglovitov
Apr 18, 2020·Molecular Autism·Aaron Gordon, Daniel H Geschwind
Jun 4, 2020·Molecular Autism·Danijela DrakulicAdrian J Harwood
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Nov 7, 2019·Scientific Reports·Emeline CrutcherChristian P Schaaf
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May 1, 2020·Trends in Neurosciences·Eric CourchesneNathan E Lewis
May 18, 2021·Biochemistry. Biokhimii︠a︡·Irina S BokshaGulnur Sh Burbaeva

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Methods Mentioned

BETA
RNA-Seq
density-gradient centrifugation
Fluorescence

Software Mentioned

Primer3
BrainSpan
R package WGCNA
Sequencher
IPA
Zeiss Blue
STAR Aligner
BiNGO
Neuroexplorer
PeakFinder

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