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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

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Abstract

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.

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Acknowledgments

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.

Funding

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.

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Authors and Affiliations

  1. Neuroscience Division, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy

    Anna Gandaglia, Elena Brivio, Sara Carli, Michela Palmieri, Francesco Bedogni, Gilda Stefanelli, Chiara Cattaneo, Marco Cicerone, Veronica Bianchi, Patrizia D’Adamo & Nicoletta Landsberger

  2. Department of Stress Neurobiology and Neurogenetics, Max Planck Institute of Psychiatry, International Max Planck Research School for Translational Psychiatry, 80804, Munich, Germany

    Elena Brivio

  3. Department of Psychology, University of Toronto Mississauga, Mississauga, Ontario, L5L 1C6, Canada

    Gilda Stefanelli

  4. Department of Biotechnology and Life Sciences, University of Insubria, 21052, Busto Arsizio, VA, Italy

    Anna Bergo, Barbara Leva & Charlotte Kilstrup-Nielsen

  5. Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands

    Chiara Cattaneo

  6. Department of Medical Biotechnology and Translational Medicine, University of Milan, 20100, Milan, Italy

    Lara Pizzamiglio, Flavia Antonucci, Angelisa Frasca & Nicoletta Landsberger

  7. Istituto di Chimica del Riconoscimento Molecolare, CNR (ICRM-CNR), 20131, Milan, Italy

    Ilda D’Annessa

  8. Department of Informatics, Institute of Computational Science, Università della Svizzera Italiana, 6900, Lugano, Switzerland

    Daniele Di Marino

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  1. Anna Gandaglia
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  2. Elena Brivio
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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.

Corresponding author

Correspondence to Nicoletta Landsberger.

Ethics declarations

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.

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Gandaglia, A., Brivio, E., Carli, S. et al. 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. Mol Neurobiol 56, 4838–4854 (2019). https://doi.org/10.1007/s12035-018-1412-2

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