Rz. Chen et al., Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice, NAT GENET, 27(3), 2001, pp. 327-331
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.