Alk3/Bmpr1a Receptor Is Required for Development of the Atrioventricular Canal Into Valves and Annulus Fibrosus

Abstract

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. Key Words: bone morphogenetic protein signaling Ⅲ heart development Ⅲ atrioventricular canal Ⅲ Cre-lox system I n humans, abnormalities in atrioventricular (AV) valves are among the most frequent congenital heart defects, 1 which reflects the complexity of the mechanisms regulating the development of the valvular apparatus. In mouse embryos, the first visible manifestation of this process is the formation of endocardial cushions in the AV canal (AVC) around E9.5 ( Figure 1A). This is a well-documented event that requires inducting signaling by the adjacent AV myocardium. [2][3][4][5][6] Recent lineage studies showed that mature AV valves are formed almost entirely from these endocardial cushions. 7,8 Interestingly, however, these cushions remain in contact with the AV myocardium throughout leaflet formation. Indeed, the mural leaflets of both AV valves are supported by AV myocardium at their ventricular side (Figure 1A). This myocardium remains as late as E17.5 when it is removed by apoptosis. 7 The septal leaflet of the tricupsid valve remains in contact with the septum ( Figure 1A) until E17.5 when it delaminates. 7 The mitral septal leaflet is never supported by myocardium at its ventricular side ( Figure 1A), but is in contact with the AV myocardium-derived mitral gully at its anterior and posterior margins (anterior and posterior in reference to the heart correspond to cranial and caudal in respect to the body). 7 The fact that the AV myocardium remains in contact with the developing leaflets suggests that it plays a role during valvular morphogenesis in addition to its original inductive role in cushion formation.Signaling molecules originating from the AV myocar...

Transcription factor genes Smad4 and Gata4 cooperatively regulate cardiac valve development

“…At least eight Tgf-β or Bmp ligands are expressed during valve formation (3,4), and gene ablation of individual ligands in model organisms produces phenotypes that range from pronounced valvuloseptal malformations to subtle valve maturation defects (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Compound gene ablations of Bmp5/Bmp7 or Bmp6/Bmp7 produced more severe endocardial cushion defects than either single mutant did (16)(17)(18).…”

The Tbx2 + Primary Myocardium of the Atrioventricular Canal Forms the Atrioventricular Node and the Base of the Left Ventricle

“…Consequently, the relation between the embryonic AVC and the definitive AV node and other structures has remained unclear. 1,8,23,36,37 The cGata6-Cre;R26R analyses 10,12 represented the first genetic fate maps of the AVC. However, because the expression pattern of the randomly integrated Cre driver was incomplete and variable, and has not been compared with the recombination pattern, lineage relations and aberrant expression of Cre could not be distinguished.…”

Activation of the Bone Morphogenetic Protein Receptor by H11Kinase/Hsp22 Promotes Cardiac Cell Growth and Survival

“…10 Besides this "canonical" pathway, the BMP receptor also activates "noncanonical," ie, Smad-independent, mediators, such as the transforming growth factor-␤-activated kinase (TAK)1. 11 Although BMP signaling is crucial for normal cardiac development, 9,12 its role in the postnatal heart remains unclear. Our results show that a potentiation of the BMP receptor pathway by H11K promotes the activation of PI3K/Akt through TAK1 activation, which dictates the physiological effects of H11K on cardiac cell growth and survival in the postnatal heart.…”