title: Ectopic Noggin in a Population of Nfatc1 Lineage Endocardial Progenitors Induces Embryonic Lethality.
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. UsingNfatc1Creto drive lineage-restricted Noggin within the endocardium, we show that ectopicNogginarrests 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-mediateddiphtheria toxin fragment-Aexpression 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.
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Paige
authors.initials: P
authors.lastname: Snider
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Simmons
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Chinh Q
authors.initials: CQ
authors.lastname: Hoang
authors.affiliation: Developmental Biology and Neonatal Medicine Program, HB Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
keywords: Nfatc1; Noggin; cardiac endocardial cushions; endocardium-cardiomyocyte cross-talk; mouse embryo; transgenic overexpression