Koshelev, M, Sarma, S, Price, RE, Wehrens, XH and Cooper, TA. Heart-specific overexpression of CUGBP1 reproduces functional and molecular abnormalities of myotonic dystrophy type 1. Hum Mol Genet 19: 1066-1075

Department of Pathology, Baylor College of Medicine, Houston, TX 77030, USA.
Human Molecular Genetics (Impact Factor: 6.39). 03/2010; 19(6):1066-75. DOI: 10.1093/hmg/ddp570
Source: PubMed


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. © The Author 2010. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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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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    • "In striated muscle, changes in CELF-mediated alternative splicing have been directly linked to disease symptoms (Charlet-B et al., 2002; Savkur et al., 2001). Over-expression of CELF1 in heart or skeletal muscle in transgenic mice recapitulates many of the alternative splicing defects and clinical features of DM1 in those tissues (Ho et al., 2004; Koshelev et al., 2010; Timchenko et al., 2004; Ward et al., 2010). Transcripts that are dysregulated in the DM1 brain have been shown to be targets of CELF-mediated alternative splicing regulation, including several exons of the microtubule binding protein tau (MAPT) and N-methyl-D-aspartate receptor (NMDAR1) exon 5 (Jiang et al., 2004; Leroy et al., 2006a,b; Sergeant et al., 2001; Vermesch et al., 1996). "
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    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".
    Full-text · Article · Dec 2012 · Molecular and Cellular Neuroscience
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    • "Thus, the developmental regulation of some DM-targeted exons may be achieved by modulating the levels of two antagonistic splicing factors, MBNL1 and CELF1. Although this MBNL loss-of-function model for DM1 and DM2 is supported by the splicing patterns observed in the skeletal and heart muscles of mouse Mbnl1 knockouts and Celf1 overexpression transgenics (Du et al., 2010; Kanadia et al., 2003; Koshelev et al., 2010; Ward et al., 2010), it is not clear whether alternative splicing in the brain is similarly dysregulated . Moreover, the view that DM is solely a spliceopathy has been recently challenged (Sicot et al., 2011). "
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    ABSTRACT: The RNA-mediated disease model for myotonic dystrophy (DM) proposes that microsatellite C(C)TG expansions express toxic RNAs that disrupt splicing regulation by altering MBNL1 and CELF1 activities. While this model explains DM manifestations in muscle, less is known about the effects of C(C)UG expression on the brain. Here, we report that Mbnl2 knockout mice develop several DM-associated central nervous system (CNS) features including abnormal REM sleep propensity and deficits in spatial memory. Mbnl2 is prominently expressed in the hippocampus and Mbnl2 knockouts show a decrease in NMDA receptor (NMDAR) synaptic transmission and impaired hippocampal synaptic plasticity. While Mbnl2 loss did not significantly alter target transcript levels in the hippocampus, misregulated splicing of hundreds of exons was detected using splicing microarrays, RNA-seq, and HITS-CLIP. Importantly, the majority of the Mbnl2-regulated exons examined were similarly misregulated in DM. We propose that major pathological features of the DM brain result from disruption of the MBNL2-mediated developmental splicing program.
    Preview · Article · Aug 2012 · Neuron
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