Article

Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1.

Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.68). 03/2010; 19(6):1066-75. DOI: 10.1093/hmg/ddp570
Source: PubMed

ABSTRACT Myotonic dystrophy type 1 (DM1) is caused by a CTG expansion within the 3'-untranslated region of the DMPK gene. The predominant mechanism of pathogenesis is a toxic gain of function of CUG repeat containing RNA transcribed from the expanded allele. The molecular mechanisms by which the RNA containing expanded repeats produce pathogenic effects include: sequestration of muscleblind-like 1 (MBNL1) protein and up-regulation of CUG binding protein 1 (CUGBP1). MBNL1 and CUGBP1 are RNA binding proteins that regulate alternative splicing transitions during development. Altered functions of these proteins in DM1 lead to misregulated splicing of their target genes, resulting in several features of the disease. The role of MBNL1 depletion in DM1 is well established through a mouse knock-out model that reproduces many disease features. Here we directly test the hypothesis that CUGBP1 up-regulation also contributes to manifestations of DM1. Using tetracycline-inducible CUGBP1 and heart-specific reverse tetracycline trans-activator transgenes, we expressed human CUGBP1 in adult mouse heart. Our results demonstrate that up-regulation of CUGBP1 is sufficient to reproduce molecular, histopathological and functional changes observed in a previously described DM1 mouse model that expresses expanded CUG RNA repeats as well as in individuals with DM1. These results strongly support a role for CUGBP1 up-regulation in DM1 pathogenesis.

Download full-text

Full-text

Available from: Satyam Sarma, Jun 24, 2015
0 Followers
 · 
276 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Alternative splicing is an important mechanism for generating transcript and protein diversity. In the brain, alternative splicing is particularly prevalent, and alternative splicing factors are highly enriched. These include the six members of the CUG-BP, Elav-like family (CELF). This review summarizes what is known about the expression of different CELF proteins in the nervous system and the evidence that they are important in neural development and function. The involvement of CELF proteins in the pathogenesis of a number of neurodegenerative disorders, including myotonic dystrophy, spinocerebellar ataxia, fragile X syndrome, spinal muscular atrophy, and spinal and bulbar muscular atrophy is discussed. Finally, the known targets of CELF-mediated alternative splicing regulation in the nervous system and the functional consequences of these splicing events are reviewed. This article is part of a Special Issue entitled "RNA and splicing regulation in neurodegeneration".
    Molecular and Cellular Neuroscience 12/2012; 56. DOI:10.1016/j.mcn.2012.12.003 · 3.73 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: RNA-binding proteins (RBPs) are key players of posttranscriptional regulation occurring during normal tissue development. All tissues examined thus far have revealed the importance of RBPs in the regulation of complex networks involved in organ morphogenesis, maturation, and function. They are responsible for controlling tissue-specific gene expression by regulating alternative splicing, mRNA stability, translation, and poly-adenylation. The heart is the first organ form during embryonic development and is also the first to acquire functionality. Numerous remodeling processes take place during late cardiac development since fetal heart first adapts to birth and then undergoes a transition to adult functionality. This physiological remodeling involves transcriptional and posttranscriptional networks that are regulated by RBPs. Disruption of the normal regulatory networks has been shown to cause cardiomyopathy in humans and animal models. Here we review the complexity of late heart development and the current information regarding how RBPs control aspects of postnatal heart development. We also review how activities of RBPs are modulated adding complexity to the regulation of developmental networks.
    Advances in Experimental Medicine and Biology 01/2014; 825:389-429. DOI:10.1007/978-1-4939-1221-6_11 · 2.01 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: During postnatal development the heart undergoes a rapid and dramatic transition to adult function through transcriptional and post-transcriptional mechanisms, including alternative splicing (AS). Here we perform deep RNA-sequencing on RNA from cardiomyocytes and cardiac fibroblasts to conduct a high-resolution analysis of transcriptome changes during postnatal mouse heart development. We reveal extensive changes in gene expression and AS that occur primarily between postnatal days 1 and 28. Cardiomyocytes and cardiac fibroblasts show reciprocal regulation of gene expression reflecting differences in proliferative capacity, cell adhesion functions and mitochondrial metabolism. We further demonstrate that AS plays a role in vesicular trafficking and membrane organization. These AS transitions are enriched among targets of two RNA-binding proteins, Celf1 and Mbnl1, which undergo developmentally regulated changes in expression. Vesicular trafficking genes affected by AS during normal development (when Celf1 is downregulated) show a reversion to neonatal splicing patterns after Celf1 re-expression in adults. Short-term Celf1 induction in adult animals results in disrupted transverse tubule organization and calcium handling. These results identify potential roles for AS in multiple aspects of postnatal heart maturation, including vesicular trafficking and intracellular membrane dynamics.
    Nature Communications 04/2014; 5:3603. DOI:10.1038/ncomms4603. · 10.74 Impact Factor