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. 3–12), 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Rett, V.A. Uber ein eigenartiges hirnatrophisches Syndrom bei Hyperammonamie im Kindesalter. Weiner Medizinische Wochenschrift 37, 723–726 (1966).
Hagberg, B., Aicardi, J., Dias, K. & Ramos, O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett's syndrome: report of 35 cases. Ann. Neurol. 14, 471–479 (1983).
Amir, R.E. et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genet. 23, 185–188 (1999).
Amir, R.E. et al. Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes. Ann. Neurol. 47, 670–679 (2000).
Wan, M. et al. Rett syndrome and beyond: recurrent spontaneous and familial MECP2 mutations at CpG hotspots. Am. J. Hum. Genet. 65, 1520–1529 (1999).
Bienvenu, T. et al. MECP2 mutations account for most cases of typical forms of Rett syndrome. Hum. Mol. Genet. 9, 1377–1284 (2000).
Cheadle, J.P. et al. Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: correlation of disease severity with mutation type and location. Hum. Mol. Genet. 9, 1119–1129 (2000).
Hampson, K., Woods, C.G., Latip, F. & Webb, T. Mutations in the MECP2 gene in a cohort of girls with Rett syndrome. J. Med. Genet. 37, 610–612 (2000).
Huppke, P., Laccone, F., Kramer, N., Engel, W. & Hanefeld, F. Rett syndrome: analysis of MECP2 and clinical characterization of 31 patients. Hum. Mol. Genet. 9, 1369–1375 (2000).
Obata, K. et al. Mutation analysis of the methyl-CpG-binding protein 2 gene (MECP2) in patients with Rett syndrome. J. Med. Genet. 37, 608–610 (2000).
Xiang, F. et al. Mutation screening in Rett syndrome patients. J. Med. Genet. 37, 250–255 (2000).
Buyse, I.M. et al. Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: identification of several novel mutations and polymorphisms. Am. J. Hum. Genet. 67, 1428–1436 (2000).
Lewis, J.D. et al. Purification, sequence and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992).
Nan, X., Tate, P., Li, E. & Bird, A.P. DNA methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421 (1996).
Nan, X., Campoy, J. & Bird, A. MeCP2 is a transcriptional repressor with abundant binding sites in genomic chromatin. Cell 88, 471–481 (1997).
Nan, X. et al. Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex. Nature 393, 386–389 (1998).
Jones, P.L. et al. Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nature Genet. 19, 187–191 (1998).
Tate, P., Skarnes, W. & Bird, A. The methyl-CpG binding protein MeCP2 is essential for embryonic development in the mouse. Nature Genet. 12, 205–208 (1996).
Meehan, R.R., Lewis, J.D., McKay, S., Kleiner, E.L. & Bird, A.P. Identification of a mammalian protein that binds specifically to DNA containing methylated CpGs. Cell 58, 499–507 (1989).
Ng, H.-H. et al. MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nature Genet. 23, 58–61 (1999).
Sauer, B. & Henderson, N. Site-specific DNA recombination in mammalian cells by the Cre recombinase of bacteriophage P1. Proc. Natl. Acad. Sci. USA 86, 5166–5170 (1988).
Schwenk, F., Baron, U. & Rajewsky, K.A. cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res. 23, 5080–5081 (1995).
Tronche, F. et al. Disruption of the glucocorticoid receptor gene in the nervous system results in reduced anxiety. Nature Genet. 23, 99–103 (1999).
Hendrich, B., Guy, J., Ramsahoye, B., Wilson, V.A. & Bird, A. Closely related proteins MBD2 and MBD3 play distinctive but interacting roles in mouse development. Genes Dev. (in press).
Fujita, N. et al. Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol. Cell. Biol. 19, 6415–6426 (1999).
Ng, H.-H., Jeppesen, P. & Bird, A. Active repression of methylated genes by the chromosomal protein MBD1. Mol. Cell. Biol. 20, 1394–1406 (2000).
Crawley, J.N. et al. Behavioural phenotypes of inbred mouse strains: implications and recommendations for molecular studies. Psychopharmacology 132, 107–124 (1997).
Chen, R., Akbarian, S., Tudor, M. & Jaenisch, R. Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice. Nature Genet. 27, 327–331 (2001).
Yusufzai, T.M. & Wolffe, A.P. Functional consequences of Rett syndrome mutations on human MeCP2. Nucleic Acids Res. 28, 4172–4179 (2000).
Free, A. et al. DNA recognition by the methyl-CpG binding domain of MeCP2. J. Biol. Chem. (in press).
Rogers, D.C. et al. Behavioral and functional analysis of mouse phenotype: SHIRPA, a proposed protocol for comprehensive phenotype assessment. Mamm. Genome 8, 711–713 (1997).
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.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/85899
This article is cited by
-
The developmental timing of spinal touch processing alterations predicts behavioral changes in genetic mouse models of autism spectrum disorders
Nature Neuroscience (2024)
-
Control of CRK-RAC1 activity by the miR-1/206/133 miRNA family is essential for neuromuscular junction function
Nature Communications (2022)
-
Evidence that direct inhibition of transcription factor binding is the prevailing mode of gene and repeat repression by DNA methylation
Nature Genetics (2022)
-
Aberrant astrocyte protein secretion contributes to altered neuronal development in multiple models of neurodevelopmental disorders
Nature Neuroscience (2022)
-
A perspective on molecular signalling dysfunction, its clinical relevance and therapeutics in autism spectrum disorder
Experimental Brain Research (2022)