Rett syndrome linked to defects in forming the MeCP2/Rbfox/LASR complex in mouse models
| Autor: | Yuhan Zhang, Hong Zhu, Wei-Kang Wang, Jingyi Hui, Ji-Song Guan, Yan Jiang, Jinsong Li, Xing Fu, Ping Wu, Catherine C. L. Wong, Lin Zhang, Ying Huang, Shen-Fei Wang, Jinbiao Ma |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities Methyl-CpG-Binding Protein 2 Protein subunit Science General Physics and Astronomy RNA-binding protein Rett syndrome Nerve Tissue Proteins RNA-binding proteins Biology General Biochemistry Genetics and Molecular Biology Heterogeneous-Nuclear Ribonucleoproteins Article MECP2 Mice Protein Domains mental disorders medicine Rett Syndrome Animals Humans Gene Cell Nucleus Multidisciplinary Alternative splicing General Chemistry Exons medicine.disease Cell biology nervous system diseases Alternative Splicing Disease Models Animal Protein Subunits HEK293 Cells Multiprotein Complexes RNA splicing Synaptic plasticity Mutation Female RNA Splicing Factors |
| Zdroj: | Nature Communications, Vol 12, Iss 1, Pp 1-16 (2021) Nature Communications |
| ISSN: | 2041-1723 |
| Popis: | 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. MeCP2 mutations can cause Rett syndrome, a severe childhood neurological disorder. Here the authors show that MeCP2 mediates the higher-order assembly of a large splicing complex Rbfox/LASR, which is disrupted in the mouse models of Rett syndrome. |
| Databáze: | OpenAIRE |
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