Dataset Information

Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.

ABSTRACT:

Background

Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that display complicated behavioral symptoms.

Methods

Using gene expressing profiling and the weighted gene co-expression network analysis (WGCNA), we studied genes coregulated by similar factors such as genetic variants or environmental effects in the hippocampus in an animal model of autism.

Results

From microarray data, we identified 21,388 robustly expressed genes of which 721 genes were found to be differently expressed in the valproic acid-treated group compared to the control group. WGCNA identified multiple co-expression modules known to associate with cognitive function, inflammation, synaptic, and positive regulation of protein kinase activating. Many of these modules, however, have not been previously linked to autism spectrum disorders which included G-protein signaling, immunity, and neuroactive ligand-receptor interaction pathway. The downregulation of the highly connected (hub) genes Taar7h and Taar7b in neuroactive ligand-receptor interaction pathway was validated by qRT-PCR. Immunoblotting and immunohistochemistry further showed that TAAR7 expression was downregulated not only in valproic acid-treated animals, but also BTBR T+tf/J mice.

Conclusions

This study highlights the advantages of gene microarrays to uncover co-expression modules associated with autism and suggests that Taars and related gene regulation networks may play a significant role in autism.

SUBMITTER: Huang JY

PROVIDER: S-EPMC6492815 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Publications

Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.

Huang Ji-Yun JY Tian Yun Y Wang Hui-Juan HJ Shen Hong H Wang Huan H Long Sen S Liao Mei-Hua MH Liu Zhi-Rong ZR Wang Ze-Ming ZM Li Dan D Tao Rong-Rong RR Cui Tian-Tian TT Moriguchi Shigeki S Fukunaga Kohji K Han Feng F Lu Ying-Mei YM

CNS neuroscience & therapeutics 20160620 10

<h4>Background</h4>Autism spectrum disorders (ASDs) are a heterogeneous group of neurodevelopmental disorders that display complicated behavioral symptoms.<h4>Methods</h4>Using gene expressing profiling and the weighted gene co-expression network analysis (WGCNA), we studied genes coregulated by similar factors such as genetic variants or environmental effects in the hippocampus in an animal model of autism.<h4>Results</h4>From microarray data, we identified 21,388 robustly expressed genes of wh ...[more]

PMID: 27321591

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Project description:BackgroundDysregulated protein kinase signaling is involved in the pathogenesis of many chronic diseases. However, the dysregulated signaling pathways critical to prion pathogenesis remain incompletely characterized. Global analyses of signaling pathways may be useful to better characterize these pathways. We therefore set out to develop such global assays. To this end, we used as a model cytoplasmic mutants of the cellular prion protein (PrPC), which are toxic to N2a neuroblastoma cells. We tested the global assays for their sensitivity to detect changes in signaling pathways in cells expressing cytoplasmic PrP mutants.MethodsWe developed a targeted proteomics (kinomics) approach using multiplex Western blots to identify signaling pathways dysregulated in chronic neurological pathologies. We tested the approach for its potential ability to detect signaling changes in N2a cells expressing cytoplasmic PrP mutants.ResultsMultiplex Western blots were designed to quantitate the expression levels of 137 protein kinases in a single membrane and using only 1.2 mg of sample. The response of the blots was sensitive and linear to changes of 6% in protein levels. Hierarchical and functional clustering of the relative expression levels identified an mTOR signaling pathway as potentially dysregulated in N2a cells expressing cytoplasmic PrP. The mTOR signaling pathway regulates global protein synthesis, which is inhibited in cells expressing cytoplasmic PrP. The levels of proteins involved in the Akt1/p70S6K branch of mTOR signaling changed in synchrony with time of cytoplasmic PrP expression. Three kinases in this pathway, Akt, p70S6K, and eIF4B were in their inactive states, as evaluated by phosphorylation of their regulatory sites.ConclusionThe results presented are consistent with the previously reported inhibition of Akt/p70S6K/eIF4B signaling as mediating pathogenesis of cytoplasmic PrP. We conclude that the kinomic analyses are sensitive and specific to detect signaling pathways dysregulated in a simple in vitro model of PrP pathogenesis.

Dataset Information

Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.

Background

Methods

Results

Conclusions

Publications

Functional Genomic Analyses Identify Pathways Dysregulated in Animal Model of Autism.

Similar Datasets

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