Molecular Neurobiology

, Volume 56, Issue 7, pp 4838–4854 | Cite as

A Novel Mecp2Y120D Knock-in Model Displays Similar Behavioral Traits But Distinct Molecular Features Compared to the Mecp2-Null Mouse Implying Precision Medicine for the Treatment of Rett Syndrome

  • Anna Gandaglia
  • Elena Brivio
  • Sara Carli
  • Michela Palmieri
  • Francesco Bedogni
  • Gilda Stefanelli
  • Anna Bergo
  • Barbara Leva
  • Chiara Cattaneo
  • Lara Pizzamiglio
  • Marco Cicerone
  • Veronica Bianchi
  • Charlotte Kilstrup-Nielsen
  • Ilda D’Annessa
  • Daniele Di Marino
  • Patrizia D’Adamo
  • Flavia Antonucci
  • Angelisa Frasca
  • Nicoletta LandsbergerEmail author


MeCP2 is a fundamental protein associated with several neurological disorders, including Rett syndrome. It is considered a multifunctional factor with a prominent role in regulating chromatin structure; however, a full comprehension of the consequences of its deficiency is still lacking. Here, we characterize a novel mouse model of Mecp2 bearing the human mutation Y120D, which is localized in the methyl-binding domain. As most models of Mecp2, the Mecp2Y120D mouse develops a severe Rett-like phenotype. This mutation alters the interaction of the protein with chromatin, but surprisingly, it also impairs its association with corepressors independently on the involved interacting domains. These features, which become overt mainly in the mature brain, cause a more accessible and transcriptionally active chromatin structure; conversely, in the Mecp2-null brain, we find a less accessible and transcriptionally inactive chromatin. By demonstrating that different MECP2 mutations can produce concordant neurological phenotypes but discordant molecular features, we highlight the importance of considering personalized approaches for the treatment of Rett syndrome.


MeCP2 Rett syndrome Mouse models Chromatin accessibility Chromatin binding 



We are extremely grateful to Giovanni Tonon and Simona Segalla (San Raffaele Scientific Institute) for their helpful technical suggestions. Part of this work was carried out in ALEMBIC, an advanced microscopy laboratory established by IRCCS Ospedale San Raffaele and Università Vita-Salute San Raffaele.

Author Contributions

A.G and N. L conceptualized and designed most of the study. P.D-A and F.A. assisted the design and realization of the behavioral and electrophysiological studies, respectively. A.G., E.B., A.B., B.L., C.C., S.C., G.S., L.P., V.B., F.B., M.P., and M.C. conducted the experiments, prepared most of the figures, and revised the manuscript. A.F. helped with statistical analysis of data. N.L. wrote the manuscript with the assistance of A.F. D.D-M, I.D., and C.K-N assisted in interpreting and discussing results.

Funding Information

This work was mainly supported by the Italian parents’ association “pro RETT ricerca” to N.L. Financial support was from Fondazione Telethon, Italy (Grant no. GGP16015 to F.A.). Functional experiments were supported by the Italian Ministry of Research and Education program “FIRB giovani” 2010, protocol number RBFR10ZBYZ. Fondazione Veronesi (Milan, Italy) provided additional funding to F.B.

Compliance with Ethical Standards

Research involving animals was performed in accordance with the European Community Council Directive 2010/63/UE for care and use of experimental animals; all the protocols were approved by the Italian Minister for Scientific Research and by the San Raffaele Scientific Institutional Animal Care and Use Committee in accordance with the Italian law.

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2018_1412_MOESM1_ESM.pdf (570 kb)
ESM 1 (PDF 570 KB)


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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Anna Gandaglia
    • 1
  • Elena Brivio
    • 1
    • 2
  • Sara Carli
    • 1
  • Michela Palmieri
    • 1
  • Francesco Bedogni
    • 1
  • Gilda Stefanelli
    • 1
    • 3
  • Anna Bergo
    • 4
  • Barbara Leva
    • 4
  • Chiara Cattaneo
    • 1
    • 5
  • Lara Pizzamiglio
    • 6
  • Marco Cicerone
    • 1
  • Veronica Bianchi
    • 1
  • Charlotte Kilstrup-Nielsen
    • 4
  • Ilda D’Annessa
    • 7
  • Daniele Di Marino
    • 8
  • Patrizia D’Adamo
    • 1
  • Flavia Antonucci
    • 6
  • Angelisa Frasca
    • 6
  • Nicoletta Landsberger
    • 1
    • 6
    Email author
  1. 1.Neuroscience DivisionIRCCS San Raffaele Scientific InstituteMilanItaly
  2. 2.Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of PsychiatryInternational Max Planck Research School for Translational PsychiatryMunichGermany
  3. 3.Department of PsychologyUniversity of Toronto MississaugaMississaugaCanada
  4. 4.Department of Biotechnology and Life SciencesUniversity of InsubriaBusto ArsizioItaly
  5. 5.Department of Molecular Oncology and Immunologythe Netherlands Cancer InstituteAmsterdamThe Netherlands
  6. 6.Department of Medical Biotechnology and Translational MedicineUniversity of MilanMilanItaly
  7. 7.Istituto di Chimica del Riconoscimento Molecolare, CNR (ICRM-CNR)MilanItaly
  8. 8.Department of Informatics, Institute of Computational ScienceUniversità della Svizzera ItalianaLuganoSwitzerland

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