Bmp Signaling Regulates Myocardial Differentiation from Cardiac Progenitors Through a MicroRNA-Mediated Mechanism

Jun Wang, Stephanie B. Greene, Margarita Bonilla-Claudio, Ye Tao, Jue Zhang, Yan Bai, Zheng Huang, Brian L. Black, Fen Wang, James F. Martin

Research output: Contribution to journalArticle

125 Scopus citations

Abstract

MicroRNAs (miRNAs) are small, noncoding RNAs that regulate gene expression posttranscriptionally. We investigated the hypothesis that bone morphogenetic protein (Bmp) signaling regulates miRNAs in cardiac progenitor cells. Bmp2 and Bmp4 regulate OFT myocardial differentiation via regulation of the miRNA-17-92 cluster. In Bmp mutant embryos, myocardial differentiation was delayed, and multiple miRNAs encoded by miRNA-17-92 were reduced. We uncovered functional miRNA-17-92 seed sequences within the 3' UTR of cardiac progenitor genes such as Isl1 and Tbx1. In both Bmp and miRNA-17-92 mutant embryos, Isl1 and Tbx1 expression failed to be correctly downregulated. Transfection experiments indicated that miRNA-17 and miRNA-20a directly repressed Isl1 and Tbx1. Genetic interaction studies uncovered a synergistic interaction between miRNA-17-92 cluster and Bmp4, providing direct in vivo evidence for the Bmp-miRNA-17-92 regulatory pathway. Our findings indicate that Bmp signaling directly regulates a miRNA-mediated effector mechanism that downregulates cardiac progenitor genes and enhances myocardial differentiation.

Original languageEnglish (US)
Pages (from-to)903-912
Number of pages10
JournalDevelopmental Cell
Volume19
Issue number6
DOIs
StatePublished - Dec 14 2010
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Developmental Biology
  • Cell Biology

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