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

Rett syndrome (RTT) is a severe neurological disorder which is mainly caused by mutations found in the X-linked gene encoding MeCP2. Despite extensive studies, the molecular functions of MeCP2 remain elusive. Here, we report that MeCP2 is a new subunit of a higher-order multiunit protein complex Rbfox/LASR and acts as a scaffold for this splicing complex. Deletion or mutation of MeCP2 leads to defects in forming MeCP2/Rbfox/LASR complex and aberrant alternative pre-mRNA splicing. Our data link RTT to an impaired function of MeCP2 in splicing control through its role in nucleating Rbfox/LASR macromolecule assembly. In this study, we performed RNA-seq, ChIP-seq and iCLIP-seq using HEK293T cells or mouse brain tissues.