Transcriptome profiling in Engrailed2 knockout mice reveals common molecular pathways associated with ASD.. Mus musculus

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 dysregulated in ASD. 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: En2-/- and WT cerebellar and hippocampal tissue from 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 the BIOBASE ExPlain system and mouse phenotype ontology database. Furthermore, we performed direct enrichment analysis of ASD associated genes from the SFARI repository in our differentially expressed genes. Results: We found 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 show enrichment of ASD-associated genes significantly higher than previously reported. Among the differentially expressed genes 20 were validated by quantitative PCR. Conclusions: Our results indicate the En2-/- mouse model of ASD as an appropriate tool to investigate molecular alterations related to ASD. Overall design: En2-/- and WT cerebellar and hippocampal tissue from 3 littermates mice for each genotype was hybridized on three replicates microarrays.