Targeted delivery of an Mecp2 transgene to forebrain neurons improves the behavior of female Mecp2-deficient mice.
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.
Jugloff
Denis G M
DG
Division of Genetics and Development, Toronto Western Research Institute, Toronto, Ontario, Canada.
Vandamme
Katrina
K
Logan
Richard
R
Visanji
Naomi P
NP
Brotchie
Jonathan M
JM
Eubanks
James H
JH
D000818:Animals; D001921:Brain / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D018390:Gene Targeting; D006801:Humans; D008297:Male; D008425:Maternal Behavior; D051783:Methyl-CpG-Binding Protein 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009043:Motor Activity; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000378:metabolism*; D015518:Rett Syndrome / Q000235:genetics / Q000523:psychology* / Q000628:therapy*; D019076:Transgenes
D051783:Methyl-CpG-Binding Protein 2