Journal Article

Targeted delivery of an <i>Mecp2</i> transgene to forebrain neurons improves the behavior of female <i>Mecp2</i>-deficient mice

Denis G.M. Jugloff, Katrina Vandamme, Richard Logan, Naomi P. Visanji, Jonathan M. Brotchie and James H. Eubanks

in Human Molecular Genetics

Volume 17, issue 10, pages 1386-1396
Published in print May 2008 | ISSN: 0964-6906
Published online January 2008 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/ddn026
Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice

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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.

Journal Article.  6668 words.  Illustrated.

Subjects: Genetics and Genomics

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