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First published online 16 June 2005
doi: 10.1242/jcs.02404

Journal of Cell Science 118, 2923-2933 (2005)
Published by The Company of Biologists 2005
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Research Article

Colocalization of muscleblind with RNA foci is separable from mis-regulation of alternative splicing in myotonic dystrophy

Thai H. Ho1, Rajesh S. Savkur2, Michael G. Poulos3, Michael A. Mancini1, Maurice S. Swanson3 and Thomas A. Cooper1,4,*

1 Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
4 Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
2 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA
3 Department of Molecular Genetics and Microbiology, Powell Gene Therapy Center, University of Florida, College of Medicine, 1600 SW Archer Road, Gainesville, FL 32610-0266, USA

* Author for correspondence (e-mail: tcooper{at}bcm.tmc.edu)

Accepted 23 March 2005

Myotonic dystrophy type I (DM1), which is caused by a non-coding CTG-repeat expansion in the dystrophia myotonica-protein kinase (DMPK) gene, is an RNA-mediated disease. Expanded CUG repeats in transcripts of mutant DMPK form nuclear foci that recruit muscleblind-like (MBNL) proteins, a family of alternative splicing factors. Although transcripts of mutant DMPK and MBNL proteins accumulate in nuclear RNA foci, it is not clear whether foci formation is required for splicing mis-regulation. Here, we use a co-transfection strategy to show that both CUG and CAG repeats form RNA foci that colocalize with green fluorescent protein (GFP)-MBNL1 and endogenous MBNL1. However, only CUG repeats alter splicing of the two tested pre-mRNAs, cardiac troponin T (cTNT) and insulin receptor (IR). Using FRAP, we demonstrate that GFP-MBNL1 in CUG and CAG foci have similar half-times of recovery and fractions of immobile molecules, suggesting that GFP-MBNL1 is bound by both CUG and CAG repeats. We also find an immobile fraction of GFP-MBNL1 in DM1 fibroblasts and a similar rapid exchange in endogenous CUG RNA foci. Therefore, formation of RNA foci and disruption of MBNL1-regulated splicing are separable events.

Key words: Alternative splicing, MBNL, Muscleblind, Myotonic dystrophy




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