Mecp2-Null Mice Provide New Neuronal Targets for Rett Syndrome

Background Rett syndrome (RTT) is a complex neurological disorder that is one of the most frequent causes of mental retardation in women. A great landmark in research in this field was the discovery of a relationship between the disease and the presence of mutations in the gene that codes for the methyl-CpG binding protein 2 (MeCP2). Currently, MeCP2 is thought to act as a transcriptional repressor that couples DNA methylation and transcriptional silencing. The present study aimed to identify new target genes regulated by Mecp2 in a mouse model of RTT. Methodology/Principal Findings We have compared the gene expression profiles of wild type (WT) and Mecp2 -null (KO) mice in three regions of the brain (cortex, midbrain, and cerebellum) by using cDNA microarrays. The results obtained were confirmed by quantitative real-time PCR. Subsequent chromatin immunoprecipitation assays revealed seven direct target genes of Mecp2 bound in vivo ( Fkbp5 , Mobp , Plagl1 , Ddc , Mllt2h , Eya2 , and S100a9 ), and three overexpressed genes due to an indirect effect of a lack of Mecp2 ( Irak1 , Prodh and Dlk1 ). The regions bound by Mecp2 were always methylated, suggesting the involvement of the methyl-CpG binding domain of the protein in the mechanism of interaction. Conclusions We identified new genes that are overexpressed in Mecp2 -KO mice and are excellent candidate genes for involvement in various features of the neurological disease. Our results demonstrate new targets of MeCP2 and provide us with a better understanding of the underlying mechanisms of RTT.