Serum response factor orchestrates nascent sarcomerogenesis and silences the biomineralization gene program in the heart

Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17824-9. doi: 10.1073/pnas.0805491105. Epub 2008 Nov 12.


Our conditional serum response factor (SRF) knockout, Srf (Cko), in the heart-forming region blocked the appearance of rhythmic beating myocytes, one of the earliest cardiac defects caused by the ablation of a cardiac-enriched transcription factor. The appearance of Hand1 and Smyd1, transcription and chromatin remodeling factors; Acta1, Acta2, Myl3, and Myom1, myofibril proteins; and calcium-activated potassium-channel gene activity (KCNMB1), the channel protein, were powerfully attenuated in the Srf(CKO) mutant hearts. A requisite role for combinatorial cofactor interactions with SRF, as a major determinant for regulating the appearance of organized sarcomeres, was shown by viral rescue of SRF-null ES cells with SRF point mutants that block cofactor interactions. In the absence of SRF genes associated with biomineralization, GATA-6, bone morphogenetic protein 4 (BMP4), and periostin were strongly up-regulated, coinciding with the down regulation of many SRF dependent microRNA, including miR1, which exerted robust silencer activity over the induction of GATA-6 leading to the down regulation of BMP4 and periostin.

Publication types

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

MeSH terms

  • Animals
  • Biomarkers / metabolism
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism
  • Cell Differentiation*
  • Embryonic Stem Cells / ultrastructure
  • Extracellular Space / metabolism
  • GATA6 Transcription Factor / genetics
  • GATA6 Transcription Factor / metabolism
  • Gene Expression Regulation, Developmental
  • Gene Silencing*
  • Heart / embryology*
  • Heart Defects, Congenital / pathology
  • Mice
  • Mice, Knockout
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • Muscle Development
  • Mutation / genetics
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocardium / ultrastructure
  • Myocytes, Cardiac / cytology
  • Myocytes, Cardiac / metabolism
  • Sarcomeres / metabolism*
  • Sarcomeres / ultrastructure
  • Serum Response Factor / deficiency
  • Serum Response Factor / metabolism*


  • Biomarkers
  • Cell Adhesion Molecules
  • GATA6 Transcription Factor
  • MicroRNAs
  • Mirn1 microRNA, mouse
  • Postn protein, mouse
  • Serum Response Factor