Abstract
The initial heart is composed of a myocardial tube lined by endocardial cells. The TGFβ superfamily is known to play an important role, as BMPs from the myocardium signal to the overlying endocardium to create an environment for EMT. Subsequently, BMP and TGFβ signaling pathways synergize to form primitive valves and regulate myocardial growth. In this study, we investigated the requirement of BMP activity by transgenic over-expression of extracellular BMP antagonist Noggin. Using Nfatc1Cre to drive lineage-restricted Noggin within the endocardium, we show that ectopic Noggin arrests cardiac development in E10.5-11 embryos, resulting in small hearts which beat poorly and die by E12.5. This is coupled with hypoplastic endocardial cushions, reduced trabeculation and fewer mature contractile fibrils in mutant hearts. Moreover, Nfatc1Cre-mediated diphtheria toxin fragment-A expression in the endocardium resulted in genetic ablation and a more severe phenotype with lethality at E11 and abnormal linear hearts. Molecular analysis demonstrated that endocardial Noggin resulted in a specific alteration of TGFβ/BMP-mediated signal transduction, in that, both Endoglin and ALK1 were downregulated in mutant endocardium. Combined, these results demonstrate the cell-autonomous requirement of the endocardial lineage and function of unaltered BMP levels in facilitating endothelium-cardiomyocyte cross-talk and promoting endocardial cushion formation.
Highlights
Following differentiation from multipotent cardiac field progenitors, the endocardial cells give rise to an internal epithelial layer adjacent to the myocardium of the initially linear embryonic heart [1,2,3].They form an endocardial tube by vasculogenesis and subsequently become the endocardium of the heart [4]
To identify the endocardial targets that are altered via ectopic Noggin and the factors that may mediate endocardial-cardiomyocyte signaling during cardiac morphogenesis, we examined expression of TGF
The goal of this study was to determine the functional effects of loss of the endocardial lineage and ectopic Noggin-mediated suppression of BMP signaling during initial heart morphogenesis, trabeculation and endocardial cushion formation
Summary
Following differentiation from multipotent cardiac field progenitors, the endocardial cells give rise to an internal epithelial layer adjacent to the myocardium of the initially linear embryonic heart [1,2,3] They form an endocardial tube by vasculogenesis and subsequently become the endocardium of the heart [4]. In addition to Notch [11] and its ligands Jag and Jag2 [22], Type I BMP receptors, ALK2 and ALK3 and TGF superfamily co-factor Smad4 [23] are present in the adjacent endocardium [19,24] and are thought to initiate EMT [25] Both BMP and TGF signaling synergize with Notch to promote the transition of endothelia to mesenchyme and the mesenchymal cell invasiveness [26,27]
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