Characterization of MeCP2 Localization and a Mouse Model for RETT Syndrome

Huda Zoghbi

After a period of apparently normal development, children with Rett syndrome (RTT) lose the ability to speak and walk and develop incessant hand-wringing motions, seizures, and scoliosis. RTT is caused by mutations in the transcriptional repressor methyl-CpG-binding protein 2 (MeCP2). To explore the pathogenesis of RTT, we analyzed the spatial and temporal distribution of MeCP2 and created a mouse model of the disease. We found that the protein is highly expressed in the brain and that the appearance of MeCP2 during development correlates with neuronal maturation. This apparent importance of MeCP2 for mature but not immature neurons may help explain the delayed onset of the disease. To create a RTT mouse model, we introduced a truncating mutation that resembles a common human mutation. Mutant mice appear normal until about 6 weeks of age, when they display tremors and stereotypic forelimb motions. At later ages, the mice develop kyphosis and are prone to seizures. Mutant mice also demonstrate motor dysfunction, hypoactivity, increased anxiety-related behavior, and altered social interactions. The motor and behavioral phenotypes of this mouse model make it a valuable model for probing the molecular, epigenetic, and anatomic bases of stereotypes, motor dysfunction, and social behaviors.