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Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models

Author

Listed:
  • Yan Jiang

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Xing Fu

    (Chinese Academy of Sciences)

  • Yuhan Zhang

    (Fudan University
    Shanghai Jiao Tong University)

  • Shen-Fei Wang

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Hong Zhu

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Wei-Kang Wang

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Lin Zhang

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Ping Wu

    (Chinese Academy of Sciences)

  • Catherine C. L. Wong

    (Chinese Academy of Sciences
    Peking University)

  • Jinsong Li

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

  • Jinbiao Ma

    (Fudan University)

  • Ji-Song Guan

    (ShanghaiTech University
    Chinese Academy of Sciences)

  • Ying Huang

    (Shanghai Jiao Tong University)

  • Jingyi Hui

    (Chinese Academy of Sciences, University of Chinese Academy of Sciences)

Abstract

Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disability in young females. RTT is mainly caused by mutations found in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Despite extensive studies, the molecular mechanism underlying RTT pathogenesis is still poorly understood. Here, we report MeCP2 as a key subunit of a higher-order multiunit protein complex Rbfox/LASR. Defective MeCP2 in RTT mouse models disrupts the assembly of the MeCP2/Rbfox/LASR complex, leading to reduced binding of Rbfox proteins to target pre-mRNAs and aberrant splicing of Nrxns and Nlgn1 critical for synaptic plasticity. We further show that MeCP2 disease mutants display defective condensate properties and fail to promote phase-separated condensates with Rbfox proteins in vitro and in cultured cells. These data link an impaired function of MeCP2 with disease mutation in splicing control to its defective properties in mediating the higher-order assembly of the MeCP2/Rbfox/LASR complex.

Suggested Citation

  • Yan Jiang & Xing Fu & Yuhan Zhang & Shen-Fei Wang & Hong Zhu & Wei-Kang Wang & Lin Zhang & Ping Wu & Catherine C. L. Wong & Jinsong Li & Jinbiao Ma & Ji-Song Guan & Ying Huang & Jingyi Hui, 2021. "Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-26084-3
    DOI: 10.1038/s41467-021-26084-3
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    Cited by:

    1. Raphaël Pantier & Megan Brown & Sicheng Han & Katie Paton & Stephen Meek & Thomas Montavon & Nicholas Shukeir & Toni McHugh & David A. Kelly & Tino Hochepied & Claude Libert & Thomas Jenuwein & Tom Bu, 2024. "MeCP2 binds to methylated DNA independently of phase separation and heterochromatin organisation," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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