title: Bmp signaling regulates myocardial differentiation from cardiac progenitors through a MicroRNA-mediated mechanism.
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.
authors.affiliation: Institute of Biosciences and Technology, Texas A&M System Health Science Center, Houston, 77030, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Stephanie B
authors.initials: SB
authors.lastname: Greene
authors.forename: Margarita
authors.initials: M
authors.lastname: Bonilla-Claudio
authors.forename: Ye
authors.initials: Y
authors.lastname: Tao
authors.forename: Jue
authors.initials: J
authors.lastname: Zhang
authors.forename: Yan
authors.initials: Y
authors.lastname: Bai
authors.forename: Zheng
authors.initials: Z
authors.lastname: Huang
authors.forename: Brian L
authors.initials: BL
authors.lastname: Black
authors.forename: Fen
authors.initials: F
authors.lastname: Wang
authors.forename: James F
authors.initials: JF
authors.lastname: Martin
mesh_terms: D000818:Animals; D001483:Base Sequence; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology; D018398:Homeodomain Proteins / Q000235:genetics; D060850:LIM-Homeodomain Proteins; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism*; D032386:Myoblasts, Cardiac / Q000166:cytology* / Q000378:metabolism*; D011247:Pregnancy; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics; D014157:Transcription Factors
chemical_list: C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D018398:Homeodomain Proteins; D060850:LIM-Homeodomain Proteins; D035683:MicroRNAs; C543614:Mirn17 microRNA, mouse; C541873:Mirn92 microRNA, mouse; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D014157:Transcription Factors; C063843:insulin gene enhancer binding protein Isl-1