Rett syndrome (RTT), a leading cause of mental retardation in females, causes cognitive, motor, and social regression after an initial period of normal development. Movement disorders and stereotypical hand behavior are distinctive features in these patients. RTT is caused by loss of function mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), a transcriptional repressor that binds to methylated CpG dinucleotides. Abnormalities of the basal ganglia and dopaminergic transmission have been described in RTT, but the molecular events leading from mutation of MeCP2 to the neurologic deficits of this disorder are unknown. I am interested in the role of the basal ganglia in RTT and the function of MeCP2 and DNA methylation in these sub cortical structures. I hypothesize that specific neuronal abnormalities of gene expression in the basal ganglia are at the root of the movement disorders of RTT. I propose to use Mecp2 mutant mice generated in Dr. Zoghbi 'S lab to identify genes that are misregulated in the basal ganglia. To pursue this study, I will (1) analyze motor and stereotypical behavior in mutant mice; (2) compare gene expression in the striatum and brainstem of wild-type and mutant mice using a candidate gene approach and cDNA micro array experiments; (3) study the effects of methyl-donors known to increase DNA-methylation on the mutant mouse phenotype. These studies will begin to shed light on the pathogenesis of RTT, and lend insight into the biology of mental retardations, movement disorders, and the role of DNA methylation in brain function.
