title: BMP10 is essential for maintaining cardiac growth during murine cardiogenesis.
abstract: During cardiogenesis, perturbation of a key transition at mid-gestation from cardiac patterning to cardiac growth and chamber maturation often leads to diverse types of congenital heart disease, such as ventricular septal defect (VSD), myocardium noncompaction, and ventricular hypertrabeculation. This transition, which occurs at embryonic day (E) 9.0-9.5 in murine embryos and E24-28 in human embryos, is crucial for the developing heart to maintain normal cardiac growth and function in response to an increasing hemodynamic load. Although, ventricular trabeculation and compaction are key morphogenetic events associated with this transition, the molecular and cellular mechanisms are currently unclear. Initially, cardiac restricted cytokine bone morphogenetic protein 10 (BMP10) was identified as being upregulated in hypertrabeculated hearts from mutant embryos deficient in FK506 binding protein 12 (FKBP12). To determine the biological function of BMP10 during cardiac development, we generated BMP10-deficient mice. Here we describe an essential role of BMP10 in regulating cardiac growth and chamber maturation. BMP10 null mice display ectopic and elevated expression of p57(kip2) and a dramatic reduction in proliferative activity in cardiomyocytes at E9.0-E9.5. BMP10 is also required for maintaining normal expression levels of several key cardiogenic factors (e.g. NKX2.5 and MEF2C) in the developing myocardium at mid-gestation. Furthermore, BMP10-conditioned medium is able to rescue BMP10-deficient hearts in culture. Our data suggest an important pathway that involves a genetic interaction between BMP10, cell cycle regulatory proteins and several major cardiac transcription factors in orchestrating this transition in cardiogenesis at mid-gestation. This may provide an underlying mechanism for understanding the pathogenesis of both structural and functional congenital heart defects.
authors.affiliation: Herman B Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Hanying
authors.initials: H
authors.lastname: Chen
authors.forename: Shu
authors.initials: S
authors.lastname: Shi
authors.forename: Lourdes
authors.initials: L
authors.lastname: Acosta
authors.forename: Weiming
authors.initials: W
authors.lastname: Li
authors.forename: Jonathan
authors.initials: J
authors.lastname: Lu
authors.forename: Shideng
authors.initials: S
authors.lastname: Bao
authors.forename: Zhuang
authors.initials: Z
authors.lastname: Chen
authors.forename: Zuocheng
authors.initials: Z
authors.lastname: Yang
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Chien
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Mervin C
authors.initials: MC
authors.lastname: Yoder
authors.forename: Laura S
authors.initials: LS
authors.lastname: Haneline
authors.forename: Diego
authors.initials: D
authors.lastname: Franco
authors.forename: Weinian
authors.initials: W
authors.lastname: Shou
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D050761:Cyclin-Dependent Kinase Inhibitor p57; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D020869:Gene Expression Profiling; D005865:Gestational Age; D006321:Heart / Q000033:anatomy & histology / Q000196:embryology* / Q000502:physiology; D006330:Heart Defects, Congenital / Q000473:pathology; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D009024:Morphogenesis / Q000502:physiology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D009687:Nuclear Proteins / Q000378:metabolism; D022061:Tacrolimus Binding Protein 1A / Q000235:genetics / Q000378:metabolism
chemical_list: C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; C493964:CDKN1C protein, human; C493965:Cdkn1c protein, mouse; D017077:Culture Media, Conditioned; D050761:Cyclin-Dependent Kinase Inhibitor p57; D009687:Nuclear Proteins; D022061:Tacrolimus Binding Protein 1A