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

Pramparo, T., Lombardo, M. V., Campbell, K., Barnes, C. C., Marinero, S., Solso, S., Young, J., Mayo, M., Dale, A., Ahrens‐Barbeau, C., Murray, S. S., Lopez, L., Lewis, N., Pierce, K. and Courchesne, E. (2015) Cell cycle networks link gene expression dysregulation, mutation, and brain maldevelopment in autistic toddlers. Molecular Systems Biology, 11 (12). p. 841. ISSN 1744-4292 doi: 10.15252/msb.20156108

Abstract/Summary

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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/86885
Identification Number/DOI	10.15252/msb.20156108
Refereed	Yes
Divisions	Life Sciences > School of Psychology and Clinical Language Sciences > Department of Psychology
Publisher	EMBO press
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