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A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome

Abstract

Rett syndrome (RTT) is an inherited neurodevelopmental disorder of females that occurs once in 10,000–15,000 births1,2. Affected females develop normally for 6–18 months, but then lose voluntary movements, including speech and hand skills. Most RTT patients are heterozygous for mutations in the X-linked gene MECP2 (refs. 312), encoding a protein that binds to methylated sites in genomic DNA and facilitates gene silencing13,14,15,16,17. Previous work with Mecp2-null embryonic stem cells indicated that MeCP2 is essential for mouse embryogenesis18. Here we generate mice lacking Mecp2 using Cre-loxP technology. Both Mecp2-null mice and mice in which Mecp2 was deleted in brain showed severe neurological symptoms at approximately six weeks of age. Compensation for absence of MeCP2 in other tissues by MeCP1 (refs. 19,20) was not apparent in genetic or biochemical tests. After several months, heterozygous female mice also showed behavioral symptoms. The overlapping delay before symptom onset in humans and mice, despite their profoundly different rates of development, raises the possibility that stability of brain function, not brain development per se, is compromised by the absence of MeCP2.

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Figure 1: Disruption of mouse Mecp2 using Cre-loxP technology.
Figure 2: Phenotypes of mice with the Mecp2-null mutation.
Figure 3: Effects of Mecp2 deletion on body weight.
Figure 4: Absence of obvious genetic or biochemical interactions between MeCP2 and the methyl-CpG binding repressor Mbd2.

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Acknowledgements

We thank D. Macleod for monitoring early mouse litters; F. Tronche and G. Schütz for nestin-Cre mice; J. Manson for deleter mice; A.J.H. Smith for ES cells; L. Vizor and J. Noble for phenotypic testing; J. Anthony and I. Davis for photographing mice; A. Greig and J. Davidson for technical assisance; staff of the Anne Walker Building for animal husbandry; A. Maas for instruction on mouse blastocyst injection; and J. Seckl, W. Skarnes, S. Brown, C. Abbott, S. Kriaucionis and J. Selfridge for advice. This work was funded by The Wellcome Trust.

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Guy, J., Hendrich, B., Holmes, M. et al. A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat Genet 27, 322–326 (2001). https://doi.org/10.1038/85899

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