title: Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus.
abstract: Endocardial cushions are precursors of mature atrioventricular (AV) valves. Their formation is induced by signaling molecules originating from the AV myocardium, including bone morphogenetic proteins (BMPs). Here, we hypothesized that BMP signaling plays an important role in the AV myocardium during the maturation of AV valves from the cushions. To test our hypothesis, we used a unique Cre/lox system to target the deletion of a floxed Alk3 allele, the type IA receptor for BMPs, to cardiac myocytes of the AV canal (AVC). Lineage analysis indicated that cardiac myocytes of the AVC contributed to the tricuspid mural and posterior leaflets, the mitral septal leaflet, and the atrial border of the annulus fibrosus. When Alk3 was deleted in these cells, defects were seen in the same leaflets, ie, the tricuspid mural leaflet and mitral septal leaflet were longer, the tricuspid posterior leaflet was displaced and adherent to the ventricular wall, and the annulus fibrosus was disrupted resulting in ventricular preexcitation. The defects seen in mice with AVC-targeted deletion of Alk3 provide strong support for a role of Alk3 in human congenital heart diseases, such as Ebstein's anomaly. In conclusion, our mouse model demonstrated critical roles for Alk3 signaling in the AV myocardium during the development of AV valves and the annulus fibrosus.
authors.affiliation: Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, 185 S Orange Ave, MSB Room G-609, Newark, NJ 07103, USA. gaussivi@umdnj.edu
authors.forename: Vinciane
authors.initials: V
authors.lastname: Gaussin
authors.forename: Gregory E
authors.initials: GE
authors.lastname: Morley
authors.forename: Luk
authors.initials: L
authors.lastname: Cox
authors.forename: An
authors.initials: A
authors.lastname: Zwijsen
authors.forename: Kendra M
authors.initials: KM
authors.lastname: Vance
authors.forename: Lorin
authors.initials: L
authors.lastname: Emile
authors.forename: Yimin
authors.initials: Y
authors.lastname: Tian
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Chull
authors.initials: C
authors.lastname: Hong
authors.forename: Dina
authors.initials: D
authors.lastname: Myers
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Christophe
authors.initials: C
authors.lastname: Depre
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Richard R
authors.initials: RR
authors.lastname: Behringer
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hanks
authors.forename: Michael D
authors.initials: MD
authors.lastname: Schneider
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
authors.forename: John B E
authors.initials: JB
authors.lastname: Burch
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Vatner
mesh_terms: D000818:Animals; D052005:Bone Morphogenetic Protein Receptors, Type I; D004268:DNA-Binding Proteins / Q000235:genetics; D050993:GATA6 Transcription Factor; D006321:Heart / Q000196:embryology*; D006351:Heart Valves / Q000002:abnormalities / Q000196:embryology*; D019426:Integrases / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D017978:Receptors, Growth Factor / Q000502:physiology*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; D050993:GATA6 Transcription Factor; C494760:Gata6 protein, mouse; D017978:Receptors, Growth Factor; D014157:Transcription Factors; D017346:Protein Serine-Threonine Kinases; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I; C045073:Cre recombinase; D019426:Integrases