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J. Cardiovasc. Dev. Dis. 2014, 1(3), 214-236; doi:10.3390/jcdd1030214

Ectopic Noggin in a Population of Nfatc1 Lineage Endocardial Progenitors Induces Embryonic Lethality

Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Received: 3 October 2014 / Revised: 1 November 2014 / Accepted: 7 November 2014 / Published: 20 November 2014
(This article belongs to the Special Issue Semilunar Valve Development and Disease)
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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. View Full-Text
Keywords: mouse embryo; transgenic overexpression; Noggin; Nfatc1; cardiac endocardial cushions; endocardium-cardiomyocyte cross-talk mouse embryo; transgenic overexpression; Noggin; Nfatc1; cardiac endocardial cushions; endocardium-cardiomyocyte cross-talk
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Snider, P.; Simmons, O.; Wang, J.; Hoang, C.Q.; Conway, S.J. Ectopic Noggin in a Population of Nfatc1 Lineage Endocardial Progenitors Induces Embryonic Lethality. J. Cardiovasc. Dev. Dis. 2014, 1, 214-236.

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J. Cardiovasc. Dev. Dis. EISSN 2308-3425 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
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