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Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers

Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi‐tissue study demonstrated h...

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Autores principales: Pramparo, Tiziano, Lombardo, Michael V, Campbell, Kathleen, Barnes, Cynthia Carter, Marinero, Steven, Solso, Stephanie, Young, Julia, Mayo, Maisi, Dale, Anders, Ahrens‐Barbeau, Clelia, Murray, Sarah S, Lopez, Linda, Lewis, Nathan, Pierce, Karen, Courchesne, Eric
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2015
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704485/
https://www.ncbi.nlm.nih.gov/pubmed/26668231
http://dx.doi.org/10.15252/msb.20156108
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author Pramparo, Tiziano
Lombardo, Michael V
Campbell, Kathleen
Barnes, Cynthia Carter
Marinero, Steven
Solso, Stephanie
Young, Julia
Mayo, Maisi
Dale, Anders
Ahrens‐Barbeau, Clelia
Murray, Sarah S
Lopez, Linda
Lewis, Nathan
Pierce, Karen
Courchesne, Eric
author_facet Pramparo, Tiziano
Lombardo, Michael V
Campbell, Kathleen
Barnes, Cynthia Carter
Marinero, Steven
Solso, Stephanie
Young, Julia
Mayo, Maisi
Dale, Anders
Ahrens‐Barbeau, Clelia
Murray, Sarah S
Lopez, Linda
Lewis, Nathan
Pierce, Karen
Courchesne, Eric
author_sort Pramparo, Tiziano
collection PubMed
description Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi‐tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment.
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spelling pubmed-47044852016-01-18 Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers Pramparo, Tiziano Lombardo, Michael V Campbell, Kathleen Barnes, Cynthia Carter Marinero, Steven Solso, Stephanie Young, Julia Mayo, Maisi Dale, Anders Ahrens‐Barbeau, Clelia Murray, Sarah S Lopez, Linda Lewis, Nathan Pierce, Karen Courchesne, Eric Mol Syst Biol Articles Genetic mechanisms underlying abnormal early neural development in toddlers with Autism Spectrum Disorder (ASD) remain uncertain due to the impossibility of direct brain gene expression measurement during critical periods of early development. Recent findings from a multi‐tissue study demonstrated high expression of many of the same gene networks between blood and brain tissues, in particular with cell cycle functions. We explored relationships between blood gene expression and total brain volume (TBV) in 142 ASD and control male toddlers. In control toddlers, TBV variation significantly correlated with cell cycle and protein folding gene networks, potentially impacting neuron number and synapse development. In ASD toddlers, their correlations with brain size were lost as a result of considerable changes in network organization, while cell adhesion gene networks significantly correlated with TBV variation. Cell cycle networks detected in blood are highly preserved in the human brain and are upregulated during prenatal states of development. Overall, alterations were more pronounced in bigger brains. We identified 23 candidate genes for brain maldevelopment linked to 32 genes frequently mutated in ASD. The integrated network includes genes that are dysregulated in leukocyte and/or postmortem brain tissue of ASD subjects and belong to signaling pathways regulating cell cycle G1/S and G2/M phase transition. Finally, analyses of the CHD8 subnetwork and altered transcript levels from an independent study of CHD8 suppression further confirmed the central role of genes regulating neurogenesis and cell adhesion processes in ASD brain maldevelopment. John Wiley and Sons Inc. 2015-12-14 /pmc/articles/PMC4704485/ /pubmed/26668231 http://dx.doi.org/10.15252/msb.20156108 Text en © 2015 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Articles
Pramparo, Tiziano
Lombardo, Michael V
Campbell, Kathleen
Barnes, Cynthia Carter
Marinero, Steven
Solso, Stephanie
Young, Julia
Mayo, Maisi
Dale, Anders
Ahrens‐Barbeau, Clelia
Murray, Sarah S
Lopez, Linda
Lewis, Nathan
Pierce, Karen
Courchesne, Eric
Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
title Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
title_full Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
title_fullStr Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
title_full_unstemmed Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
title_short Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
title_sort cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4704485/
https://www.ncbi.nlm.nih.gov/pubmed/26668231
http://dx.doi.org/10.15252/msb.20156108
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