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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing / genetics*
  • Alternative Splicing / physiology
  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Conserved Sequence
  • Gene Expression Regulation
  • HEK293 Cells
  • Humans
  • MEF2 Transcription Factors / genetics*
  • MEF2 Transcription Factors / metabolism
  • Mice
  • Muscle Development / genetics*
  • Muscle Development / physiology
  • Myoblasts / physiology*
  • Organ Specificity
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA / genetics*
  • RNA-Binding Proteins / physiology*
  • Sequence Analysis, RNA
  • rho-Associated Kinases / genetics*
  • rho-Associated Kinases / metabolism


  • MEF2 Transcription Factors
  • Protein Isoforms
  • RNA-Binding Proteins
  • RNA
  • rho-Associated Kinases

Associated data

  • GEO/GSE58928