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

ABSTRACT: 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.

SUBMITTER: Pramparo T

PROVIDER: S-EPMC4704485 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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

Pramparo Tiziano T Lombardo Michael V MV Campbell Kathleen K Barnes Cynthia Carter CC Marinero Steven S Solso Stephanie S Young Julia J Mayo Maisi M Dale Anders A Ahrens-Barbeau Clelia C Murray Sarah S SS Lopez Linda L Lewis Nathan N Pierce Karen K Courchesne Eric E

Molecular systems biology 20151214 12

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 volum ...[more]

PMID: 26668231

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Project description:BackgroundStudies of early caregiver-mediated interventions targeting social communication of young autistic children have yielded variable child outcomes. This study examined the effects of combining two caregiver-mediated interventions on caregiver strategy use and child social communication and language outcomes.MethodThis was a multisite parallel randomized controlled trial. Participants included 120 caregivers and their autistic children between 24 and 36 months of age. Dyads were randomly assigned to receive a hybrid intervention that combined Enhanced Milieu Teaching (EMT) and Joint Attention, Symbolic Play, Engagement, and Regulation (JASPER) or to a behavior management control condition, each delivered over 6 months. Caregivers in the JASP-EMT group received twice-weekly, in-home, and hour-long sessions. Outcomes were measured at baseline, the end of intervention (T1), and 6 months later (T2) and included a naturalistic language sample procedure, standardized measures, and caregiver report measures. This trial was registered at clinicaltrials.gov (NCT02595697).ResultsChild outcomes did not differ between conditions at T1 or T2 for child primary (social communication) or secondary (language, play, and autism symptoms) outcomes. Relative to control group caregivers, intervention group caregivers demonstrated significantly higher use of JASP-EMT strategies at T1 and T2, with the exception of two strategies (Responsiveness and Matched Responsiveness), which were used significantly more by control group caregivers. Neither autism severity nor baseline caregiver responsiveness moderated outcomes. Post hoc analyses revealed significant correlations between specific strategies and all child outcomes.ConclusionsTwice-weekly caregiver-mediated intervention that taught caregivers of autistic children to use social communication support strategies did not yield significant child outcomes. Future studies should examine possible sources for the lack of main effects including unexpected differences in linguistic features of caregiver input, changes in control group caregiver behavior, and insufficient intervention dosage.Supplemental materialhttps://doi.org/10.23641/asha.21714278.

Dataset Information

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

Publications

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

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