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

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...

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Autores principales: DeRosa, Brooke A., El Hokayem, Jimmy, Artimovich, Elena, Garcia-Serje, Catherine, Phillips, Andre W., Van Booven, Derek, Nestor, Jonathan E., Wang, Lily, Cuccaro, Michael L., Vance, Jeffery M., Pericak-Vance, Margaret A., Cukier, Holly N., Nestor, Michael W., Dykxhoorn, Derek M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976773/
https://www.ncbi.nlm.nih.gov/pubmed/29849033
http://dx.doi.org/10.1038/s41598-018-26495-1
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author DeRosa, Brooke A.
El Hokayem, Jimmy
Artimovich, Elena
Garcia-Serje, Catherine
Phillips, Andre W.
Van Booven, Derek
Nestor, Jonathan E.
Wang, Lily
Cuccaro, Michael L.
Vance, Jeffery M.
Pericak-Vance, Margaret A.
Cukier, Holly N.
Nestor, Michael W.
Dykxhoorn, Derek M.
author_facet DeRosa, Brooke A.
El Hokayem, Jimmy
Artimovich, Elena
Garcia-Serje, Catherine
Phillips, Andre W.
Van Booven, Derek
Nestor, Jonathan E.
Wang, Lily
Cuccaro, Michael L.
Vance, Jeffery M.
Pericak-Vance, Margaret A.
Cukier, Holly N.
Nestor, Michael W.
Dykxhoorn, Derek M.
author_sort DeRosa, Brooke A.
collection PubMed
description 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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spelling pubmed-59767732018-05-31 Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons DeRosa, Brooke A. El Hokayem, Jimmy Artimovich, Elena Garcia-Serje, Catherine Phillips, Andre W. Van Booven, Derek Nestor, Jonathan E. Wang, Lily Cuccaro, Michael L. Vance, Jeffery M. Pericak-Vance, Margaret A. Cukier, Holly N. Nestor, Michael W. Dykxhoorn, Derek M. Sci Rep Article 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. Nature Publishing Group UK 2018-05-30 /pmc/articles/PMC5976773/ /pubmed/29849033 http://dx.doi.org/10.1038/s41598-018-26495-1 Text en © The Author(s) 2018 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
DeRosa, Brooke A.
El Hokayem, Jimmy
Artimovich, Elena
Garcia-Serje, Catherine
Phillips, Andre W.
Van Booven, Derek
Nestor, Jonathan E.
Wang, Lily
Cuccaro, Michael L.
Vance, Jeffery M.
Pericak-Vance, Margaret A.
Cukier, Holly N.
Nestor, Michael W.
Dykxhoorn, Derek M.
Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
title Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
title_full Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
title_fullStr Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
title_full_unstemmed Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
title_short Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons
title_sort convergent pathways in idiopathic autism revealed by time course transcriptomic analysis of patient-derived neurons
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976773/
https://www.ncbi.nlm.nih.gov/pubmed/29849033
http://dx.doi.org/10.1038/s41598-018-26495-1
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