title: Persistent Noggin arrests cardiomyocyte morphogenesis and results in early in utero lethality.
abstract: BACKGROUND
  Multiple bone morphogenetic protein (BMP) genes are expressed in the developing heart from the initiation to late-differentiation stages, and play pivotal roles in cardiovascular development. In this study, we investigated the requirement of BMP activity in heart development by transgenic over-expression of extracellular BMP antagonist Noggin.
  
  
  RESULTS
  Using Nkx2.5-Cre to drive lineage-restricted Noggin within cardiomyocyte progenitors, we show persistent Noggin arrests cardiac development at the linear heart stage. This is coupled with a significantly reduced cell proliferation rate, subsequent cardiomyocyte programmed cell death and reduction of downstream intracellular pSMAD1/5/8 expression. Noggin mutants exhibit reduced heartbeat which likely results in subsequent fully penetrant in utero lethality. Significantly, confocal and electron micrographic examination revealed considerably fewer contractile elements, as well as a lack of maturation of actin-myosin microfilaments. Molecular analysis demonstrated that ectopic Noggin-expressing regions in the early heart's pacemaker region, failed to express the potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 (Hcn4), resulting in an overall decrease in Hcn4 levels.
  
  
  CONCLUSIONS
  Combined, our results reveal a novel role for BMP signaling in the progression of heart development from the tubular heart stage to the looped stage by means of regulation of proliferation and promotion of maturation of the in utero heart's contractile apparatus and pacemaker.
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Olga
authors.initials: O
authors.lastname: Simmons
authors.forename: Paige
authors.initials: P
authors.lastname: Snider
authors.forename: Jain
authors.initials: J
authors.lastname: Wang
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Schwartz
authors.forename: Yiping
authors.initials: Y
authors.lastname: Chen
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005313:Fetal Death; D018507:Gene Expression Regulation, Developmental; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000235:genetics*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D000099176:Noggin Protein
chemical_list: D002352:Carrier Proteins; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D000099176:Noggin Protein; C578706:Hcn4 protein, mouse
keywords: BMP; Noggin; bradycardia; cardiomyocyte; congenital heart defects; contractile apparatus; mouse embryo; proliferation; transgenic overexpression