Transcriptome profiling in engrailed-2 mutant mice reveals common molecular pathways associated with autism spectrum disorders

BACKGROUND: Transcriptome analysis has been used in autism spectrum disorder (ASD) to unravel common pathogenic pathways based on the assumption that distinct rare genetic variants or epigenetic modifications affect common biological pathways. To unravel recurrent ASD-related neuropathological mechanisms, we took advantage of the En2( -/- ) mouse model and performed transcriptome profiling on cerebellar and hippocampal adult tissues. METHODS: Cerebellar and hippocampal tissue samples from three En2( -/- ) and wild type (WT) littermate mice were assessed for differential gene expression using microarray hybridization followed by RankProd analysis. To identify functional categories overrepresented in the differentially expressed genes, we used integrated gene-network analysis, gene ontology enrichment and mouse phenotype ontology analysis. Furthermore, we performed direct enrichment analysis of ASD-associated genes from the SFARI repository in our differentially expressed genes. RESULTS: Given the limited number of animals used in the study, we used permissive criteria and identified 842 differentially expressed genes in En2( -/- ) cerebellum and 862 in the En2( -/- ) hippocampus. Our functional analysis revealed that the molecular signature of En2( -/- ) cerebellum and hippocampus shares convergent pathological pathways with ASD, including abnormal synaptic transmission, altered developmental processes and increased immune response. Furthermore, when directly compared to the repository of the SFARI database, our differentially expressed genes in the hippocampus showed enrichment of ASD-associated genes significantly higher than previously reported. qPCR was performed for representative genes to confirm relative transcript levels compared to those detected in microarrays. CONCLUSIONS: Despite the limited number of animals used in the study, our bioinformatic analysis indicates the En2( -/- ) mouse is a valuable tool for investigating molecular alterations related to ASD.