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Radically truncated MeCP2 rescues Rett syndrome-like neurological defects

Nature volume 550, pages 398401 (19 October 2017) | Download Citation


Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome1. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine2,3. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners4, including transcriptional co-repressors (for example, the NCoR/SMRT complex5), transcriptional activators6, RNA7, chromatin remodellers8,9, microRNA-processing proteins10 and splicing factors11. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons12. At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain13 and the NCoR/SMRT interaction domain5. Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.

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  1. 1.

    et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat. Genet. 23, 185–188 (1999)

  2. 2.

    et al. Purification, sequence, and cellular localization of a novel chromosomal protein that binds to methylated DNA. Cell 69, 905–914 (1992)

  3. 3.

    et al. Neuronal MeCP2 is expressed at near histone-octamer levels and globally alters the chromatin state. Mol. Cell 37, 457–468 (2010)

  4. 4.

    & Rett syndrome: a complex disorder with simple roots. Nat. Rev. Genet. 16, 261–275 (2015)

  5. 5.

    et al. Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR/SMRT co-repressor. Nat. Neurosci. 16, 898–902 (2013)

  6. 6.

    et al. MeCP2, a key contributor to neurological disease, activates and represses transcription. Science 320, 1224–1229 (2008)

  7. 7.

    & Components of the DNA methylation system of chromatin control are RNA-binding proteins. J. Biol. Chem. 279, 49479–49487 (2004)

  8. 8.

    et al. Interaction between chromatin proteins MECP2 and ATRX is disrupted by mutations that cause inherited mental retardation. Proc. Natl Acad. Sci. USA 104, 2709–2714 (2007)

  9. 9.

    et al. MeCP2 interacts with HP1 and modulates its heterochromatin association during myogenic differentiation. Nucleic Acids Res. 35, 5402–5408 (2007)

  10. 10.

    et al. MeCP2 suppresses nuclear microRNA processing and dendritic growth by regulating the DGCR8/Drosha complex. Dev. Cell 28, 547–560 (2014)

  11. 11.

    et al. Regulation of RNA splicing by the methylation-dependent transcriptional repressor methyl-CpG binding protein 2. Proc. Natl Acad. Sci. USA 102, 17551–17558 (2005)

  12. 12.

    , , , & MECP2, a multi-talented modulator of chromatin architecture. Brief. Funct. Genomics 15, 420–431 (2016)

  13. 13.

    , & Dissection of the methyl-CpG binding domain from the chromosomal protein MeCP2. Nucleic Acids Res. 21, 4886–4892 (1993)

  14. 14.

    & The major form of MeCP2 has a novel N-terminus generated by alternative splicing. Nucleic Acids Res. 32, 1818–1823 (2004)

  15. 15.

    , , & DNA methylation specifies chromosomal localization of MeCP2. Mol. Cell. Biol. 16, 414–421 (1996)

  16. 16.

    et al. Heterogeneity in residual function of MeCP2 carrying missense mutations in the methyl CpG binding domain. J. Med. Genet. 40, 487–493 (2003)

  17. 17.

    et al. Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders. Proc. Natl Acad. Sci. USA 114, E3243–E3250 (2017)

  18. 18.

    , , , & Reversal of neurological defects in a mouse model of Rett syndrome. Science 315, 1143–1147 (2007)

  19. 19.

    et al. Postnatal inactivation reveals enhanced requirement for MeCP2 at distinct age windows. Hum. Mol. Genet. 21, 3806–3814 (2012)

  20. 20.

    et al. The molecular basis of variable phenotypic severity among common missense mutations causing Rett syndrome. Hum. Mol. Genet. 25, 558–570 (2016)

  21. 21.

    , , , & A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome. Nat. Genet. 27, 322–326 (2001)

  22. 22.

    et al. Rett syndrome mutation MeCP2 T158A disrupts DNA binding, protein stability and ERP responses. Nat. Neurosci. 15, 274–283 (2011)

  23. 23.

    et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron 35, 243–254 (2002)

  24. 24.

    et al. A partial loss of function allele of methyl-CpG-binding protein 2 predicts a human neurodevelopmental syndrome. Hum. Mol. Genet. 17, 1718–1727 (2008)

  25. 25.

    et al. Development of a novel AAV gene therapy cassette with improved safety features and efficacy in a mouse model of Rett syndrome. Mol. Ther. Methods Clin. Dev. 5, 180–190 (2017)

  26. 26.

    et al. MeCP2 recognizes cytosine methylated tri-nucleotide and di-nucleotide sequences to tune transcription in the mammalian brain. PLoS Genet. 13, e1006793 (2017)

  27. 27.

    , , & DNA methylation in the gene body influences MeCP2-mediated gene repression. Proc. Natl Acad. Sci. USA 113, 15114–15119 (2016)

  28. 28.

    et al. An AT-hook domain in MeCP2 determines the clinical course of Rett syndrome and related disorders. Cell 152, 984–996 (2013)

  29. 29.

    et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron 52, 255–269 (2006)

  30. 30.

    , , , & Loss of activity-induced phosphorylation of MeCP2 enhances synaptogenesis, LTP and spatial memory. Nat. Neurosci. 14, 1001–1008 (2011)

  31. 31.

    et al. Multiplex genome engineering using CRISPR/VCas systems. Science 339, 819–823 (2013)

  32. 32.

    & Manufacturing of recombinant adeno-associated viral vectors for clinical trials. Mol. Ther. Methods Clin. Dev. 3, 16002 (2016)

  33. 33.

    et al. Improved survival and reduced phenotypic severity following AAV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol. Ther. 21, 18–30 (2013)

  34. 34.

    et al. Phosphorylation of MeCP2 at serine 80 regulates its chromatin association and neurological function. Proc. Natl Acad. Sci. USA 106, 4882–4887 (2009)

  35. 35.

    et al. Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature 499, 341–345 (2013)

  36. 36.

    et al. MeCP2 binding to DNA depends upon hydration at methyl-CpG. Mol. Cell 29, 525–531 (2008)

  37. 37.

    , , & Sequence-specific DNA binding by AT-hook motifs in MeCP2. FEBS Lett. 590, 2927–2933 (2016)

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This work was supported by the Rett Syndrome Research Trust, Wellcome, and Sylvia Aitken Charitable Trust. R.T. was funded by a Biotechnology and Biological Sciences Research Council Doctoral Training Partnership studentship. We thank the following people for assistance: A. Cook (advice on designing the truncated proteins), A. McClure (animal husbandry), D. Kelly (microscopy), M. Waterfall (flow cytometry) and A. Kerr (statistics). We also thank members of the Bird, Cobb, M. E. Greenberg and G. Mandel laboratories for discussions. A.B. and S.R.C. are members of the Simons Initiative for the Developing Brain at the University of Edinburgh.

Author information


  1. The Wellcome Centre for Cell Biology, University of Edinburgh, Michael Swann Building, King’s Buildings, Max Born Crescent, Edinburgh EH9 3BF, UK

    • Rebekah Tillotson
    • , Jim Selfridge
    • , Martha V. Koerner
    • , Jacky Guy
    • , Dina De Sousa
    •  & Adrian Bird
  2. Institute of Neuroscience and Psychology, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK

    • Kamal K. E. Gadalla
    • , Ralph D. Hector
    •  & Stuart R. Cobb
  3. Pharmacology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt

    • Kamal K. E. Gadalla


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R.T., A.B. and S.R.C. designed research. R.T., J.S., M.V.K., K.K.E.G., J.G., D.D.S. and R.D.H. performed the experiments. R.T. and S.R.C. analysed the data. R.T. and A.B. wrote the manuscript. All authors reviewed the manuscript.

Competing interests

A.B. is a member of the Board of ArRETT, a company based in the USA with the goal of developing therapies for Rett syndrome.

Corresponding author

Correspondence to Adrian Bird.

Reviewer Information Nature thanks B. Davidson and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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