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

Zhiyv Niu, Dinakar Iyer, Simon J. Conway, James F. Martin, Kathryn Ivey, Deepak Srivastava, Alfred Nordheim, Robert J. Schwartz

Research output: Contribution to journalArticlepeer-review

81 Scopus citations

Abstract

Our conditional serum response factor (SRF) knockout, SrfCko, 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 SrfCKO 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.

Original languageEnglish (US)
Pages (from-to)17824-17829
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume105
Issue number46
DOIs
StatePublished - Nov 18 2008

Keywords

  • Cardiogenesis
  • GATA6
  • Heart development
  • MicroRNA
  • Periostin

ASJC Scopus subject areas

  • General

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