Alk3/Bmpr1a receptor is required for development of the atrioventricular canal into valves and annulus fibrosus.
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.
Gaussin
Vinciane
V
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
Morley
Gregory E
GE
Cox
Luk
L
Zwijsen
An
A
Vance
Kendra M
KM
Emile
Lorin
L
Tian
Yimin
Y
Liu
Jing
J
Hong
Chull
C
Myers
Dina
D
Conway
Simon J
SJ
Depre
Christophe
C
Mishina
Yuji
Y
Behringer
Richard R
RR
Hanks
Mark C
MC
Schneider
Michael D
MD
Huylebroeck
Danny
D
Fishman
Glenn I
GI
Burch
John B E
JB
Vatner
Stephen F
SF
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
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