title: Endothelial expression of bone morphogenetic protein receptor type 1a is required for atrioventricular valve formation.
abstract: BACKGROUND
  Atrioventricular canal defects account for 4% of all congenital heart anomalies. They arise from failure of endocardial cushion formation, a process dependent on transition of endothelial cells into clustered mesenchymal cells in the mid-atrioventricular septum. To date, the genetic signals necessary for atrioventricular canal defects are poorly understood. We hypothesized that bone morphogenetic protein signaling in cardiac endothelial cells may be crucial to this process.
  
  
  METHODS
  To study the role of bone morphogenetic protein receptors (Bmpr) in the developing heart, we created knockout mice with inactivation of Bmpr1a selectively in endocardium. Two strains of null mice were created: one with constitutive endothelial-specific knockout of Bmpr1a and one with time-inducible, endothelial-specific knockout of Bmpr1a. Embryos and animals were analyzed by microscopy, RNA in situ hybridization, and microangiography.
  
  
  RESULTS
  Animals with null mutation of Bmpr1a in endothelium were embryonic lethal at E11.5 to 12.0 and demonstrated absence of endocardial cushion formation. Embryos failed to form atrioventricular valves and adjacent septa. Endocardial knockout of Bmpr1a did not affect development of the outflow tract or aortic arches. Using time-inducible, cell-specific knockout mice, we show that Bmpr1a has two functions in the developing atrioventricular canal: to induce endocardial endothelial-mesenchymal transition, and to pattern the septal mesenchyme into endocardial cushions. We demonstrate that these processes are temporally linked to expression of the transcription factors Id1 and Id3.
  
  
  CONCLUSIONS
  Endocardial cushion formation is dependent on cell-specific expression of Bmpr1a. Our results suggest that Bmpr1a-mediated signaling is a crucial pathway involved in pathogenesis of atrioventricular septal and valve malformations, which are among the most common congenital heart defects in humans.
authors.affiliation: Division of Cardiothoracic Surgery, University of California San Diego, San Diego, California 92103-8892, USA.
authors.forename: Kan
authors.initials: K
authors.lastname: Kaneko
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Li
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Zhang
authors.forename: John J
authors.initials: JJ
authors.lastname: Lamberti
authors.forename: Stuart W
authors.initials: SW
authors.lastname: Jamieson
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Thistlethwaite
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics*; D004694:Endocardial Cushion Defects / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D054089:Endocardial Cushions / Q000196:embryology / Q000473:pathology; D004699:Endocardium / Q000196:embryology* / Q000473:pathology; D004730:Endothelium, Vascular / Q000196:embryology* / Q000473:pathology; D005260:Female; D017930:Genes, Reporter / Q000235:genetics; D007763:Lac Operon; D051379:Mice; D018345:Mice, Knockout; D035463:Pol1 Transcription Initiation Complex Proteins / Q000235:genetics; D011247:Pregnancy; D015398:Signal Transduction / Q000235:genetics
chemical_list: D035463:Pol1 Transcription Initiation Complex Proteins; C065173:TFID transcription factor; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I