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Muscleblind proteins regulate alternative splicing

Thai H Ho1, Nicolas Charlet-B, Michael G Poulos

  • 1Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX 77030, USA.

The EMBO Journal
|July 17, 2004
PubMed

Insights

Muscleblind (MBNL) proteins regulate alternative splicing of key genes, cardiac troponin T (cTNT) and insulin receptor (IR), which are misregulated in myotonic dystrophy (DM). This reveals a crucial role for MBNL proteins in DM RNA pathogenesis.

Area of Science:

  • Molecular Biology
  • Genetics
  • RNA Biology

Background:

  • The muscleblind (MBNL) protein family is linked to myotonic dystrophy (DM) pathogenesis.
  • Disrupted pre-mRNA splicing is a hallmark of DM's RNA-mediated disease model.
  • CELF proteins were previously implicated in DM pathogenesis and splicing regulation.

Purpose of the Study:

  • To elucidate the specific function of MBNL proteins in DM.
  • To investigate the role of MBNL proteins in the alternative splicing of DM-misregulated pre-mRNAs.
  • To understand the interplay between MBNL and CELF proteins in regulating splicing.

Main Methods:

  • Demonstrated MBNL protein regulation of cardiac troponin T (cTNT) and insulin receptor (IR) pre-mRNA alternative splicing.
  • Investigated the antagonistic relationship between MBNL and CELF proteins on cTNT and IR splicing.
  • Characterized distinct MBNL and CELF binding sites and MBNL's independence from CELF binding sites.

Main Results:

  • MBNL proteins oppositely regulate alternative splicing of cTNT and IR exons.
  • CELF proteins antagonize the splicing patterns promoted by MBNL for both cTNT and IR.
  • MBNL regulation of splicing does not depend on the presence of CELF-binding sites.

Conclusions:

  • MBNL proteins play a direct role in regulating alternative splicing of critical pre-mRNAs implicated in DM.
  • The findings support a model where DM pathogenesis involves loss of MBNL and/or gain of CELF activity, disrupting splicing.
  • This provides a mechanistic link between MBNL protein function and the RNA-mediated pathology of myotonic dystrophy.

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