RBM4 down-regulates PTB and antagonizes its activity in muscle cell-specific alternative splicing

J Cell Biol. 2011 May 2;193(3):509-20. doi: 10.1083/jcb.201007131. Epub 2011 Apr 25.

Abstract

Alternative splicing contributes largely to cell differentiation and functional specification. We previously reported that the RNA-binding protein RBM4 antagonizes the activity of splicing factor PTB to modulate muscle cell-specific exon selection of α-tropomyosin. Here we show that down-regulation of PTB and its neuronal analogue nPTB during muscle cell differentiation may involve alternative splicing-coupled nonsense-mediated mRNA decay. RBM4 regulates PTB/nPTB expression by activating exon skipping of their transcripts during myogenesis. Moreover, RBM4 and PTB target a common set of transcripts that undergo muscle cell-specific alternative splicing. Overexpression of RBM4 invariably promoted expression of muscle cell-specific isoforms, which recapitulated in vivo alternative splicing changes during muscle differentiation, whereas PTB acted oppositely to RBM4 in expression of mRNA isoforms specific for late-stage differentiation. Therefore, RBM4 may synergize its effect on muscle cell-specific alternative splicing by down-regulating PTB expression and antagonizing the activity of PTB in exon selection, which highlights a hierarchical role for RBM4 in a splicing cascade that regulates myogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Animals
  • Cell Line
  • Down-Regulation*
  • Exons
  • Gene Expression Regulation*
  • Humans
  • Mice
  • Muscle Development
  • Muscles / metabolism*
  • Neurons / metabolism
  • Polypyrimidine Tract-Binding Protein / antagonists & inhibitors
  • Polypyrimidine Tract-Binding Protein / metabolism*
  • Protein Isoforms
  • RNA, Messenger / metabolism
  • RNA-Binding Proteins / biosynthesis*

Substances

  • Protein Isoforms
  • RBM4 protein, human
  • RNA, Messenger
  • RNA-Binding Proteins
  • Polypyrimidine Tract-Binding Protein