title: Desmoplakin and talin2 are novel mRNA targets of fragile X-related protein-1 in cardiac muscle.
abstract: BACKGROUND
  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.
  
  
  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.
authors.affiliation: Department of Cellular and Molecular Medicine, University of Arizona, 1656 East Mabel, Tucson, AZ 85724, USA.
authors.forename: Samantha A
authors.initials: SA
authors.lastname: Whitman
authors.forename: Cathleen
authors.initials: C
authors.lastname: Cover
authors.forename: Lily
authors.initials: L
authors.lastname: Yu
authors.forename: David L
authors.initials: DL
authors.lastname: Nelson
authors.forename: Daniela C
authors.initials: DC
authors.lastname: Zarnescu
authors.forename: Carol C
authors.initials: CC
authors.lastname: Gregorio
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D054974:Costameres / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D051180:Desmoplakins / Q000235:genetics* / Q000378:metabolism; D003896:Desmosomes / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007382:Intermediate Filaments / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D051379:Mice; D018345:Mice, Knockout; D008854:Microscopy, Electron; D032383:Myocytes, Cardiac / Q000473:pathology / Q000502:physiology* / Q000648:ultrastructure; D009210:Myofibrils / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D014176:Protein Biosynthesis / Q000502:physiology; D012323:RNA Processing, Post-Transcriptional / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D012518:Sarcomeres / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D016608:Talin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051180:Desmoplakins; C495295:Dsp protein, mouse; C496283:Fxr1h protein, mouse; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C518833:TLN2 protein, mouse; D016608:Talin