Human Molecular Genetics Advance Access originally published online on January 25, 2008
Human Molecular Genetics 2008 17(10):1386-1396; doi:10.1093/hmg/ddn026
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Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice
1 Division of Genetics and Development 2 Division of Brain Imaging and Behavior, Toronto Western Research Institute, Toronto, Ontario, Canada M5T 2S8 3 University of Toronto Epilepsy Research Program 4 Department of Surgery (Neurosurgery), University of Toronto, Toronto, Ontario, Canada M5S 1A8
* To whom correspondence should be addressed: Tel: +1 4166035800 ext. 2933; Fax: +1 4166035745; Email: jeubanks{at}uhnres.utoronto.ca
Received October 29, 2007; Accepted January 18, 2008
Rett syndrome is an X-linked neurological condition affecting almost exclusively girls that is caused by mutations of the MECP2 gene. Recent studies have shown that transgenic delivery of MeCP2 function to Mecp2-deficient male mice can improve their Rett-like behavior. However, as the brain of a Rett girl contains a mosaic of MeCP2 expressing and non-expressing neurons, and the over-expression of MeCP2 in neurons can induce a severe progressive neurological phenotype, testing whether functional rescue can be achieved by gene re-introduction strategies in a female model of Rett syndrome is warranted. To address this, we generated transgenic mice expressing an epitope-tagged Mecp2 transgene in forebrain neurons. These mice over-express MeCP2 protein at about 1.6 times normal levels in cortex and develop impaired motor behavior by 9–12 months of age. To test whether forebrain-targeted MeCP2 restoration would improve behavior in female Mecp2–/+ mice, we crossed these transgenics with Mecp2–/+ mice and examined the behavioral properties of the female rescue mice for 1 year. These assessments revealed that the diminished rearing activity, impaired mobility and the diminished locomotive activity of female Mecp2–/+ mice were restored to wild-type levels in the rescue mice. These results show that improvement of Rett-like behavior can be achieved in Mecp2–/+ females by targeted gene re-introduction without inducing deficits relating to MeCP2 over-expression.