Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice

Mecp2 is an X-linked gene encoding a nuclear protein that binds specificall y to methylated DNA (ref. 1) and functions as a general transcriptional rep ressor by associating with chromatin-remodeling complexes(2,3) Mecp2 is exp ressed at high levels in the postnatal brain(1,4), indicating that methylat ion-dependent regulation of gene expression may have a crucial role in the mammalian central nervous system. Consistent with this notion is the recent demonstration that MECP2 mutations cause Rett syndrome(5-8) (RTT, MIM 3127 50), a childhood neurological disorder that represents one of the most comm on causes of mental retardation in females(9-11) Here we show that Mecp2-de ficient mice exhibit phenotypes that resemble some of the symptoms of RTT p atients. Mecp2-null mice were normal until 5 weeks of age, when they began to develop disease, leading to death between 6 and 12 weeks. Mutant brains showed substantial reduction in both weight and neuronal cell size, but no obvious structural defects or signs of neurodegeneration. Brain-specific de letion of Mecp2 at embryonic day resulted in a phenotype identical to that of the null mutation, indicating that the phenotype is caused by Mecp2 defi ciency in the CNS rather than in perpherial tissues. Deletion of Mecp2 in p ostnatal CNS neurons led to a similar neuronal phenotype, although at a lat er age. Our results indicate that role of Mecp2 is not restricted to the im mature brain, but becomes critical in mature neurons. Mecp2 deficiency in t hese neurons is sufficient to cause neuronal dysfunction with symptomatic m anifestation similar to Rett syndrome.