title: Expression of the BMP receptor Alk3 in the second heart field is essential for development of the dorsal mesenchymal protrusion and atrioventricular septation.
abstract: BACKGROUND
  The dorsal mesenchymal protrusion (DMP) is a prong of mesenchyme derived from the second heart field (SHF) located at the venous pole of the developing heart. Recent studies have shown that perturbation of its development is associated with the pathogenesis of atrioventricular (AV) septal defect. Although the importance of the DMP to AV septation is now established, the molecular and cellular mechanisms underlying its development are far from fully understood. Prior studies have demonstrated that bone morphogenetic protein (BMP) signaling is essential for proper formation of the AV endocardial cushions and the cardiac outflow tract. A role for BMP signaling in regulation of DMP development remained to be elucidated.
  
  
  OBJECTIVE
  To determine the role of BMP signaling in DMP development.
  
  
  RESULTS
  Conditional deletion of the BMP receptor Alk3 from venous pole SHF cells leads to impaired formation of the DMP and a completely penetrant phenotype of ostium primum defect, a hallmark feature of AV septal defects. Analysis of mutants revealed decreased proliferative index of SHF cells and, consequently, reduced number of SHF cells at the cardiac venous pole. In contrast, volume and expression of markers associated with proliferation and active BMP/transforming growth factor β signaling were not significantly altered in the AV cushions of SHF-Alk3 mutants.
  
  
  CONCLUSIONS
  BMP signaling is required for expansion of the SHF-derived DMP progenitor population at the cardiac venous pole. Perturbation of Alk3-mediated BMP signaling from the SHF results in impaired development of the DMP and ostium primum defects.
authors.affiliation: Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Briggs
authors.forename: Aimee L
authors.initials: AL
authors.lastname: Phelps
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Brown
authors.forename: Jayant
authors.initials: J
authors.lastname: Kakarla
authors.forename: Robert H
authors.initials: RH
authors.lastname: Anderson
authors.forename: Maurice J B
authors.initials: MJ
authors.lastname: van den Hoff
authors.forename: Andy
authors.initials: A
authors.lastname: Wessels
mesh_terms: D000818:Animals; D054087:Atrial Septum / Q000196:embryology* / Q000502:physiology; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics* / Q000378:metabolism; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D006343:Heart Septal Defects / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006344:Heart Septal Defects, Atrial / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008648:Mesoderm / Q000196:embryology / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology; D054088:Ventricular Septum / Q000196:embryology* / Q000502:physiology
chemical_list: D019485:Bone Morphogenetic Proteins; D049452:Green Fluorescent Proteins; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: Alk3; atrial septal defect; atrioventricular septal defect; bone morphogenetic protein; dorsal mesenchymal protrusion