Young JI, Hong EP, Castle JC, Crespo-Barreto J, Bowman AB, Rose MF, Kang D, Richman R, Johnson JM, Berget S, Zoghbi HY.
Departments of Molecular and Human Genetics, Neurology, Neuroscience, and Pediatrics, Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Programs in Cellular and Molecular Biology and Developmental Biology, and Howard Hughes Medical Institute, Baylor College of Medicine, Houston, TX 77030.Abstract
This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected on April 20, 2004. Rett syndrome (RTT) is a postnatal neurodevelopmental disorder characterized by the loss of acquired motor and language skills, autistic features, and unusual stereotyped movements. RTT is caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2). Mutations in MECP2 cause a variety of neurodevelopmental disorders including X-linked mental retardation, psychiatric disorders, and some cases of autism. Although MeCP2 was identified as a methylation-dependent transcriptional repressor, transcriptional profiling of RNAs from mice lacking MeCP2 did not reveal significant gene expression changes, suggesting that MeCP2 does not simply function as a global repressor. Changes in expression of a few genes have been observed, but these alterations do not explain the full spectrum of Rett-like phenotypes, raising the possibility that additional MeCP2 functions play a role in pathogenesis. In this study, we show that MeCP2 interacts with the RNA-binding protein Y box-binding protein 1 and regulates splicing of reporter minigenes. Importantly, we found aberrant alternative splicing patterns in a mouse model of RTT. Thus, we uncovered a previously uncharacterized function of MeCP2 that involves regulation of splicing, in addition to its role as a transcriptional repressor.Lay Summary
As we all know, the leading cause of RTT is sporadic mutations in the MeCP2 gene. The resulting MeCP2 protein is believed to play a pivotal role in silencing other genes. It is believed that the inability to shut down specific genes causes the cascade of symptoms seen in RTT. However, efforts to identify MeCP2 target genes have limited success - there just doesn't seem to be the global changes in gene expression that was originally expected. In this key paper, the authors took a fresh look at MeCP2, and sought to identify proteins that interact with MeCP2, with the hope of revealing new functional roles for MeCP2. Excitingly, they identified a new MeCP2 partner - Y box-binding protein (YB-1). YB-1 has many cellular functions - one of which is alternative splicing. Alternative splicing is the process that occurs in cells where the readout from single gene - or its mRNA transcript - can be "edited" to create slightly different mRNA transcripts. That is, thanks to alternative splicing, several flavors (proteins) can be produced from a single recipe (gene). Indeed, different alternative splicing patterns for numerous genes were identified in a mouse model of RTT. Thus, the authors have uncovered a previously uncharacterized function of MeCP2 that involves the regulation of splicing, shedding new light on the underlying mechanisms of RTT.