Loss of MeCP2 function is associated with distinct gene expression changes in the striatum

Rett syndrome (RTT) is a neurodevelopmental disorder characterized by developmental regression beginning 6-18months after birth, followed by a lifetime of intellectual disability, stereotyped behaviors, and motor deficits. RTT is caused by mutations in the gene encoding MeCP2, a methyl-CpG binding protein believed to modulate gene transcription. Gene expression studies of individual brain regions have reported that Mecp2 loss-of-function leads to both activation and repression of its gene targets in mice. Conditional deletion of MeCP2 from different brain regions has revealed unique insights into the role of these structures in mediating particular RTT-like phenotypes. However, the function of MeCP2 in the striatum, a major brain region involved in motor control and executive cognitive functions, has yet to be studied. Here, we characterized the gene expression changes in the striatum of Mecp2 mutant mice. We found a number of differentially expressed genes in the striatum of both constitutive Mecp2-null mice and mice lacking MeCP2 only from forebrain GABAergic neurons. These changes only occurred when MeCP2 expression levels had reached mature levels and RTT-like symptoms were manifest, supporting a role for MeCP2 in maintaining proper brain function. Many of the gene expression changes identified in the striatum have not previously been shown to change in the hypothalamus or cerebellum. Bioinformatic analysis of differentially expressed genes in striatum as well as hypothalamus and cerebellum revealed that loss of MeCP2 does not affect the global landscape of gene expression. Additionally, we uncovered a number of differentially expressed genes in the liver of Mecp2-null mice suggesting an important role for MeCP2 in non-neuronal tissues. Collectively, our data suggest that the differential expression of genes following loss of MeCP2 occurs in a tissue- or cell-type specific manner and thus MeCP2 function should be understood in a cellular context.