title: Myocardin regulates BMP10 expression and is required for heart development.
abstract: Myocardin is a muscle lineage-restricted transcriptional coactivator that has been shown to transduce extracellular signals to the nucleus required for SMC differentiation. We now report the discovery of a myocardin/BMP10 (where BMP10 indicates bone morphogenetic protein 10) signaling pathway required for cardiac growth, chamber maturation, and embryonic survival. Myocardin-null (Myocd) embryos and embryos harboring a cardiomyocyte-restricted mutation in the Myocd gene exhibited myocardial hypoplasia, defective atrial and ventricular chamber maturation, heart failure, and embryonic lethality. Cardiac hypoplasia was caused by decreased cardiomyocyte proliferation accompanied by a dramatic increase in programmed cell death. Defective chamber maturation and the block in cardiomyocyte proliferation were caused in part by a block in BMP10 signaling. Myocardin transactivated the Bmp10 gene via binding of a serum response factor-myocardin protein complex to a nonconsensus CArG element in the Bmp10 promoter. Expression of p57kip2, a BMP10-regulated cyclin-dependent kinase inhibitor, was induced in Myocd-/- hearts, while BMP10-activated cardiogenic transcription factors, including NKX2.5 and MEF2c, were repressed. Remarkably, when embryonic Myocd-/- hearts were cultured ex vivo in BMP10-conditioned medium, the defects in cardiomyocyte proliferation and p57kip2 expression were rescued. Taken together, these data identify a heretofore undescribed myocardin/BMP10 signaling pathway that regulates cardiomyocyte proliferation and apoptosis in the embryonic heart.
authors.affiliation: University of Pennsylvania, Cardiovascular Institute, Department of Medicine, Philadelphia, PA 19104-5159, USA.
authors.forename: Jianhe
authors.initials: J
authors.lastname: Huang
authors.forename: John
authors.initials: J
authors.lastname: Elicker
authors.forename: Nina
authors.initials: N
authors.lastname: Bowens
authors.forename: Xi
authors.initials: X
authors.lastname: Liu
authors.forename: Lan
authors.initials: L
authors.lastname: Cheng
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Cappola
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zhu
authors.forename: Michael S
authors.initials: MS
authors.lastname: Parmacek
mesh_terms: D000818:Animals; D017209:Apoptosis; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis* / Q000235:genetics; D002454:Cell Differentiation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005318:Fetal Heart / Q000000981:diagnostic imaging / Q000254:growth & development* / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D006330:Heart Defects, Congenital / Q000235:genetics / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D009924:Organ Culture Techniques; D038081:Organogenesis / Q000235:genetics; D015398:Signal Transduction; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D015533:Transcriptional Activation; D014463:Ultrasonography; D000099251:Myocardin
chemical_list: D019485:Bone Morphogenetic Proteins; D017077:Culture Media, Conditioned; D009687:Nuclear Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000099251:Myocardin; C119152:Bmp10 protein, mouse