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.
Highlights
Induced pluripotent stem cells have emerged as a powerful tool for modeling a variety of human diseases, including genetically complex psychiatric disorders7–11. iPSC lines can be generated directly from clinically defined patients, allowing the complete genetic profile of the individual to be replicated in the iPSC line, www.nature.com/scientificreports/
Six male non-Hispanic white (NHW) individuals with idiopathic autism spectrum disorders (ASDs) were selected for iPSC reprogramming (Table 1)
The first is that it employs a model that consists of idiopathic ASD-specific iPSCs differentiated into cortical neurons, thereby generating a largely inaccessible cell type directly from ASD patients
Summary
Induced pluripotent stem cells (iPSCs) have emerged as a powerful tool for modeling a variety of human diseases, including genetically complex psychiatric disorders7–11. iPSC lines can be generated directly from clinically defined patients, allowing the complete genetic profile of the individual to be replicated in the iPSC line, www.nature.com/scientificreports/. The in vitro differentiation of human iPSCs into regionally-specific, well-defined, subtypes of neurons mimics the same neurodevelopmental processes that occur during in vivo neurogenesis, when regional patterning is taking place in the developing cerebral cortex[13] This makes iPSC-derived neurons well-suited for modeling human neurodevelopmental conditions such as ASD as they offer an experimental platform for studying the cellular and molecular mechanisms that give rise to the disorder, and that underlie its progression at the onset of pathogenesis during prenatal and early postnatal brain development. Evidence indicates that dysregulation of gene expression patterns, copy number variations, splicing and long non-coding RNA could influence ASD susceptibility Most of these studies used either immortalized cell lines or postmortem brain tissue which each have limitations in how efficiently they model neurodevelopmental disorders such as ASD5,15–22.
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