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

doi:10.1016/j.devcel.2010.10.022

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 journal › Article › peer-review

155 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 language	English (US)
Pages (from-to)	903-912
Number of pages	10
Journal	Developmental Cell
Volume	19
Issue number	6
DOIs	https://doi.org/10.1016/j.devcel.2010.10.022
State	Published - Dec 14 2010

ASJC Scopus subject areas

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

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10.1016/j.devcel.2010.10.022

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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.",

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

note = "Funding Information: We thank S. Evans and R. Kelly for in situ probes, L. Ma for early experiments, and E. Tzahor for discussions. Supported by NIH grants 2R01DE12324-12 and R01HL093484-01 (J.F.M.), T32 DE15355-04 (M.B.-C.), and CA096824 (F.W.); AHA0655077Y from The American Heart Association (F.W.). J.W. was supported by grant 09PRE2150024 from the South Central Affiliate of the American Heart Association. ",

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AU - Wang, Jun

AU - Greene, Stephanie B.

AU - Bonilla-Claudio, Margarita

AU - Tao, Ye

AU - Zhang, Jue

AU - Bai, Yan

AU - Huang, Zheng

AU - Black, Brian L.

AU - Wang, Fen

AU - Martin, James F.

N1 - Funding Information: We thank S. Evans and R. Kelly for in situ probes, L. Ma for early experiments, and E. Tzahor for discussions. Supported by NIH grants 2R01DE12324-12 and R01HL093484-01 (J.F.M.), T32 DE15355-04 (M.B.-C.), and CA096824 (F.W.); AHA0655077Y from The American Heart Association (F.W.). J.W. was supported by grant 09PRE2150024 from the South Central Affiliate of the American Heart Association.

PY - 2010/12/14

Y1 - 2010/12/14

N2 - 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.

AB - 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.

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

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