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

• Published in: Nature communications Vol. 12; no. 1; p. 5767
• Main Authors: Jiang, Yan, Fu, Xing, Zhang, Yuhan, Wang, Shen-Fei, Zhu, Hong, Wang, Wei-Kang, Zhang, Lin, Wu, Ping, Wong, Catherine C. L., Li, Jinsong, Ma, Jinbiao, Guan, Ji-Song, Huang, Ying, Hui, Jingyi
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 14/19; 38/91; 631/337/1645/1946; 631/45/612/1230; 64; 64/60; 82/83; Alternative Splicing - genetics; Animal models; Animals; Assembly; Cell Nucleus - metabolism; Children; Condensates; Data links; Disease control; Disease Models, Animal; Exons - genetics; Female; HEK293 Cells; Heterogeneous-Nuclear Ribonucleoproteins - metabolism; Humanities and Social Sciences; Humans; Intellectual disabilities; MeCP2 protein; Methyl-CpG binding protein; Methyl-CpG-Binding Protein 2 - chemistry; Methyl-CpG-Binding Protein 2 - metabolism; Mice; multidisciplinary; Multiprotein Complexes - metabolism; Mutation; Mutation - genetics; Nerve Tissue Proteins - genetics; Neurological diseases; Neurological disorders; Pathogenesis; Protein Domains; Protein Subunits - metabolism; Proteins; Rett syndrome; Rett Syndrome - genetics; RNA Splicing Factors - metabolism; Science; Science (multidisciplinary); Splicing; Synaptic plasticity
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-26084-3

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.