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Transcriptome Profiling in Engrailed2 Knockout Mice Reveals Common Molecular Pathways Associated with Autism Spectrum Disorders

Saturday, May 17, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
P. Sgad1, G. Provenzano1, E. Dassi2, V. Adami3, G. Zunino1, S. Genovesi1, S. Casarosa4 and Y. Bozzi1, (1)Molecular Neuropathology Laboratory, Centre for Integrative Biology (CIBIO), University of Trento, Italy, Trento, Italy, (2)Laboratory of Translational Genomics, Centre for Integrative Biology (CIBIO), University of Trento, Italy, Trento, Italy, (3)High Throughput Screening Core Facility, Centre for Integrative Biology (CIBIO), University of Trento, Italy, Trento, Italy, (4)Laboratory of Developmental Neurobiology, Centre for Integrative Biology (CIBIO), University of Trento, Italy, Trento, Italy
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. 

Objectives: 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 samples from three 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 show enrichment of ASD-associated genes significantly higher than previously reported. qPCR was used with 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 as a valuable tool to investigate molecular alterations related to ASD.

See more of: Animal Models
See more of: Animal Models