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

Yan Jiang,Lin Zhang,Catherine C L Wong,Ping Wu,Jinbiao Ma,Jinsong Li,Ying Huang,Jingyi Hui,Ji-Song Guan,Hong Zhu,Yuhan Zhang,Xing Fu,Shen-Fei Wang,Wei-Kang Wang

doi:10.1038/s41467-021-26084-3

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.

Highlights

Rett syndrome (RTT) is a severe neurological disorder and a leading cause of intellectual disability in young females
methyl-CpG binding protein 2 (MeCP2) showed no interactions with NF90, hnRNP A1, and hnRNP K, which are absent in large assembly of splicing regulators (LASR) complex, indicating that the interactions between MeCP2 and components of RBFOX2/LASR are specific
These results indicate that MeCP2 is a subunit of the previously identified RBFOX2/LASR complex

Summary

Introduction

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). 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 Nlgn[1] 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. The mechanism underlying MeCP2-mediated splicing regulation in RTT has remained largely elusive

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Conclusion