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Mol Cell. 2014 Aug 21;55(4):592-603. doi: 10.1016/j.molcel.2014.06.035. Epub 2014 Jul 31.

Rbfox2-coordinated alternative splicing of Mef2d and Rock2 controls myoblast fusion during myogenesis.

Author information

1
Departments of Pathology and Immunology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
2
Departments of Molecular and Cellular Biology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
3
Departments of Dan L. Duncan Cancer Center, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
4
The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
5
University of Ljubljana, Faculty of Computer and Information Science, Trẑaŝka cesta 25, SI-1000 Ljubljana.
6
Department of Molecular Neuroscience, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
7
Departments of Molecular Physiology and Biophysics, Baylor College of Medicine, Medicine, Houston, Texas 77030, USA.
#
Contributed equally

Abstract

Alternative splicing plays important regulatory roles during periods of physiological change. During development, a large number of genes coordinately express protein isoform transitions regulated by alternative splicing; however, the mechanisms that coordinate splicing and the functional integration of the resultant tissue-specific protein isoforms are typically unknown. Here we show that the conserved Rbfox2 RNA binding protein regulates 30% of the splicing transitions observed during myogenesis and is required for the specific step of myoblast fusion. Integration of Rbfox2-dependent splicing outcomes from RNA-seq with Rbfox2 iCLIP data identified Mef2d and Rock2 as Rbfox2 splicing targets. Restored activities of Mef2d and Rock2 rescued myoblast fusion in Rbfox2-depleted cultures, demonstrating functional cooperation of protein isoforms generated by coordinated alterative splicing. The results demonstrate that coordinated alternative splicing by a single RNA binding protein modulates transcription (Mef2d) and cell signaling (Rock2) programs to drive tissue-specific functions (cell fusion) to promote a developmental transition.

PMID:
25087874
PMCID:
PMC4142074
DOI:
10.1016/j.molcel.2014.06.035
[Indexed for MEDLINE]
Free PMC Article

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