Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2.
In humans, mutations in the X-linked MECP2 gene, are the cause of Rett syndrome (RTT), a neurodevelopmental disorder that affects mainly girls. MeCP2 binds to methylated CpGs and is thought to act as a transcriptional repressor. In male mice, deletion or targeted mutation of Mecp2 leads to lethality and causes a neuronal phenotype. Selective mutation of Mecp2 in postnatal neurons results in a similar, although delayed, phenotype, suggesting that the symptoms are caused by MeCP2 deficiency in postmitotic neurons. In agreement with this idea, expression of a Mecp2 transgene in postmitotic neurons of Mecp2-null mutant mice resulted in the phenotypical rescue of the symptoms. To assess whether postnatal activation of MeCP2 in mutant animals could also affect the progression of the disorder, we constructed a conditionally active Mecp2 "rescue transgene" that was activated between P0 and P30. The Mecp2 transgene was under the control of the CAGGS promoter and was activated by using brain specific Cre-mediated recombination. Our results indicate that postnatal, neuron-specific activation of MeCP2 as late as 2-4 weeks of age significantly prolonged the lifespan of mutant animals and delayed the onset of neurologic symptoms.
Giacometti
Emanuela
E
Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA.
Luikenhuis
Sandra
S
Beard
Caroline
C
Jaenisch
Rudolf
R
D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D015518:Rett Syndrome / Q000235:genetics* / Q000401:mortality
C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2