CUGBP1 overexpression in mouse skeletal muscle reproduces features of myotonic dystrophy type 1

Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 09/2010; 19(18):3614-22. DOI: 10.1093/hmg/ddq277
Source: PubMed


The neuromuscular disease myotonic dystrophy type I (DM1) affects multiple organ systems with the major symptoms being severe
muscle weakness, progressive muscle wasting and myotonia. The causative mutation in DM1 is a CTG repeat expansion in the 3′-untranslated
region of the DM protein kinase (DMPK) gene. RNA transcribed from the expanded allele contains the expanded CUG repeats and leads to the nuclear depletion of Muscleblind-like
1 (MBNL1) and to the increased steady-state levels of CUG-binding protein 1 (CUGBP1). The pathogenic effects of MBNL1 depletion
have previously been tested by the generation of MBNL1 knockout mice, but the consequence of CUGBP1 overexpression in adult
muscle is not known. In a DM1 mouse model expressing RNA containing 960 CUG repeats in skeletal muscle, CUGBP1 up-regulation
is temporally correlated with severe muscle wasting. In this study, we generated transgenic mice with doxycycline-inducible
and skeletal muscle-specific expression of CUGBP1. Adult mouse skeletal muscle overexpressing CUGBP1 reproduces molecular
and physiological defects of DM1 tissue. The results from this study strongly suggest that CUGBP1 has a major role in DM1
skeletal muscle pathogenesis.

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Available from: James M Killian, Apr 01, 2015
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    • "Notably, MBNL1 knockout mice display myotonia due to abnormal CLCN1 splicing and develop myopathy, but exhibit no sign of muscle degeneration [26]. On the other hand, induced expression of CUGBP1 in adult skeletal muscle or the heart also mimics DM1 histopathology [27], [28]. Microarray analysis has identified mis-splicing events in the skeletal muscle of the HSALR mouse (FVB/n strain) that expresses approximately 250 CUG-repeats [14]. "
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    ABSTRACT: With the goal of identifying splicing alterations in myotonic dystrophy 1 (DM1) tissues that may yield insights into targets or mechanisms, we have surveyed mis-splicing events in three systems using a RT-PCR screening and validation platform. First, a transgenic mouse model expressing CUG-repeats identified splicing alterations shared with other mouse models of DM1. Second, using cell cultures from human embryonic muscle, we noted that DM1-associated splicing alterations were significantly enriched in cytoskeleton (e.g. SORBS1, TACC2, TTN, ACTN1 and DMD) and channel (e.g. KCND3 and TRPM4) genes. Third, of the splicing alterations occurring in adult DM1 tissues, one produced a dominant negative variant of the splicing regulator RBFOX1. Notably, half of the splicing events controlled by MBNL1 were co-regulated by RBFOX1, and several events in this category were mis-spliced in DM1 tissues. Our results suggest that reduced RBFOX1 activity in DM1 tissues may amplify several of the splicing alterations caused by the deficiency in MBNL1.
    Full-text · Article · Sep 2014 · PLoS ONE
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    • "The CELF (CUGBP and Etr-like factors) family proteins are major sequence-specific RNA binding proteins that control alternative splicing and mRNA translation and stability [6,7]. Some reports have demonstrated that CELF1 protein regulates pre-mRNA alternative splicing and is involved in mRNA editing and translation [8-10]. Whether the expression of the CELF1 gene is related to the proliferation of human lung cancer has not been investigated. "
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    ABSTRACT: Lung cancer is the leading cause of cancer-related death in the world, with metastasis as the main reason for the mortality. CELF1 is an RNA-binding protein controlling the post-transcriptional regulation of genes related to cell survival. As yet, there is little knowledge of CELF1 expression and biological function in lung cancer. This study investigated the expression levels of CELF1 in lung cancer tissues and the biological function of CELF1 in lung cancer cells. CELF1 mRNA expression was determined in lung cancer and normal tissues, and the relationship between the expression level of CELF1 and clinicopathological parameters was evaluated. The biological function of CELF1 in A549 and H1299 lung cancer cell lines growth was examined. The expression of CELF1 was higher in human lung cancer tissues compared with the normal lung tissue. Lentiviral-mediated transfection of CELF1 siRNA effectively silenced the expression of CELF1 in both A549 and H1299 cells. Moreover, CELF1 knockdown markedly reduced the survival rate of lung cancer cells. Colony formation assays revealed a reduction in the number and size of lung cancer cell colonies from CELF1 knockdown. These results indicated that CELF1 may have significant roles in the progression of lung cancer, and suggested that siRNA mediated silencing of CELF1 could be an effective tool in lung cancer treatment.
    Full-text · Article · Nov 2013 · Cancer Cell International
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    • "We found a robust and statistically significant change of 13.5% increase in exon 7a inclusion in Clcn1, a 7.4% increase in Nfix exon 7 inclusion, a 16.2% increase in Smyd1 exon 39 inclusion, a 16.9% decrease in Nrap exon 12 inclusion, and a 11.9% increase in Mbnl1 exon 5 inclusion (Figure 3C). Some of these targets such as Mbnl1 exon 5, Clcn1 exon 7 and Nfix exon 7 are known to be specifically regulated by MBNL1, suggesting that the EDM1 mice containing the DM5 transgene do have MBNL1 sequestration, even if it is not evident in discrete nuclear foci [18], [22], [23]. "
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    ABSTRACT: Myotonic dystrophy type 1 (DM1) is the most common muscular dystrophy in adults. It is caused by an expanded (CTG)n tract in the 3' UTR of the Dystrophia Myotonica Protein Kinase (DMPK) gene. This causes nuclear retention of the mutant mRNA into ribonuclear foci and sequestration of interacting RNA-binding proteins (such as muscleblind-like 1 (MBNL1)). More severe congenital and childhood-onset forms of the disease exist but are less understood than the adult disease, due in part to the lack of adequate animal models. To address this, we utilized transgenic mice over-expressing the DMPK 3' UTR as part of an inducible RNA transcript to model early-onset myotonic dystrophy. In mice in which transgene expression was induced during embryogenesis, we found that by two weeks after birth, mice reproduced cardinal features of myotonic dystrophy, including myotonia, cardiac conduction abnormalities, muscle weakness, histopathology and mRNA splicing defects. Notably, these defects were more severe than in adult mice induced for an equivalent period of exposure to RNA toxicity. Additionally, the utility of the model was tested by over-expressing MBNL1, a key therapeutic strategy being actively pursued for treating the disease phenotypes associated with DM1. Significantly, increased MBNL1 in skeletal muscle partially corrected myotonia and splicing defects present in these mice, demonstrating the responsiveness of the model to relevant therapeutic interventions. Furthermore, these results also represent the first murine model for early-onset DM1 and provide a tool to investigate the effects of RNA toxicity at various stages of development.
    Full-text · Article · Sep 2013 · PLoS ONE
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