| Mutations in the X-linked methyl CpG binding protein 2 (MECP2 ) gene are the primary genetic cause underlying the neurodevelopmental disorder Rett Syndrome (RTT). The current model predicts that MeCP2 functions as a multi-faceted transcriptional regulator whose functions include recruiting chromatin remodeling enzymes to methylated cytosine residues throughout the genome to repress transcription. While the discovery of MeCP2 as the causative gene behind RTT has provided a genetic marker to diagnosis the disorder, the mechanisms linking loss of function of MeCP2 to the pathogenesis underlying RTT are largely unknown. To elucidate the molecular mechanisms behind the neuronal dysfunction caused by mutations in MeCP2, mus musculus was used as a model system to study the role of Mecp2 function in the postnatal brain. In mice, loss of Mecp2 function produces a neurological phenotype that resembles the phenotype observed in patients with RTT, including stereotypic movements, breathing irregularities, tremors, behavioral learning deficits and acquired microcephaly. In this dissertation, the expression of the Mecp2 transcripts was investigated at various postnatal ages in wildtype mouse brain. While Mecp2 transcripts were detected thoughout the anterior nervous system, by P21 the Mecp2e2 splice variant became enriched in the dorsal thalamus and cortical layer V. In contrast, our results suggest the Mecp2e1 splice variant remains widely expressed thoughout the postnatal mouse brain and is more abundant than Mecp2e2. In addition, the distribution and abundance of tyrosine hyroxylase (Th), Dlx6 and preprodynorphin were investigated in the Mecp2 knockout mice. No ectopic expression was detected in the Mecp2-/y mice, however there was a significant increase in the amount of Th enzyme present in the striatum of the Mecp2-/y mice. The significant up-regulation of Th enzyme was also accompanied by findings that demonstrated a significant reduction in the area occupied by Dlx6 labeling in the striatum. In addition, methylation within the upstream region of the Th promoter might provide a binding site for Mecp2, and the chromatin immunoprecipitation assay has shown that Mecp2 associates with portions of this upstream region. These results suggest an underlying dysfunction of the striatal dopaminergic system as a result of mutations in the Mecp2 gene. |
