Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle

Samantha A. Whitman, Cathleen Cover, Lily Yu, David L. Nelson, Daniela C. Zarnescu, Carol C. Gregorio

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

Abstract

Rationale: The proper function of cardiac muscle requires the precise assembly and interactions of numerous cytoskeletal and regulatory proteins into specialized structures that orchestrate contraction and force transmission. Evidence suggests that posttranscriptional regulation is critical for muscle function, but the mechanisms involved remain understudied. Objective: To investigate the molecular mechanisms and targets of the muscle-specific fragile X mental retardation, autosomal homolog 1 (FXR1), an RNA binding protein whose loss leads to perinatal lethality in mice and cardiomyopathy in zebrafish. Methods and Results: Using RNA immunoprecipitation approaches we found that desmoplakin and talin2 mRNAs associate with FXR1 in a complex. In vitro assays indicate that FXR1 binds these mRNA targets directly and represses their translation. Fxr1 KO hearts exhibit an up-regulation of desmoplakin and talin2 proteins, which is accompanied by severe disruption of desmosome as well as costamere architecture and composition in the heart, as determined by electron microscopy and deconvolution immunofluorescence analysis. Conclusions: Our findings reveal the first direct mRNA targets of FXR1 in striated muscle and support translational repression as a novel mechanism for regulating heart muscle development and function, in particular the assembly of specialized cytoskeletal structures.

Original languageEnglish (US)
Pages (from-to)262-271
Number of pages10
JournalCirculation research
Volume109
Issue number3
DOIs
StatePublished - Jul 22 2011

Keywords

  • cytoskeletal dynamics
  • desmosome
  • heart development
  • mRNA binding proteins

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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