title: Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development.
abstract: Formation of the coronary vasculature is a complex and precisely coordinated morphogenetic process that begins with the formation of epicardium. The epicardium gives rise to many components of the coronary vasculature, including fibroblasts, smooth muscle cells, and endothelium. Hippo signaling components have been implicated in cardiac development and regeneration. However, a role of Hippo signaling in the epicardium has not been explored. Employing a combination of genetic and pharmacological approaches, we demonstrate that inhibition of Hippo signaling mediators Yap and Taz leads to impaired epicardial epithelial-to-mesenchymal transition (EMT) and a reduction in epicardial cell proliferation and differentiation into coronary endothelial cells. We provide evidence that Yap and Taz control epicardial cell behavior, in part by regulating Tbx18 and Wt1 expression. Our findings show a role for Hippo signaling in epicardial cell proliferation, EMT, and cell fate specification during cardiac organogenesis.
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore 169857, Singapore.
authors.forename: Anamika
authors.initials: A
authors.lastname: Singh
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore 169857, Singapore.
authors.forename: Sindhu
authors.initials: S
authors.lastname: Ramesh
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore 169857, Singapore.
authors.forename: Dasan Mary
authors.initials: DM
authors.lastname: Cibi
authors.affiliation: National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609, Singapore.
authors.forename: Lim Sze
authors.initials: LS
authors.lastname: Yun
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Lauren J
authors.initials: LJ
authors.lastname: Manderfield
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9148, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Department of Cell and Developmental Biology, Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: epsteinj@upenn.edu.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
authors.affiliation: Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore 169857, Singapore; National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609, Singapore; Department of Cell and Developmental Biology, Cardiovascular Institute and Institute for Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: manvendra.singh@duke-nus.edu.sg.
authors.forename: Manvendra K
authors.initials: MK
authors.lastname: Singh
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D003331:Coronary Vessels / Q000166:cytology / Q000196:embryology* / Q000378:metabolism*; D020964:Embryo Loss / Q000378:metabolism / Q000473:pathology; D047108:Embryonic Development; D042783:Endothelial Cells / Q000166:cytology; D058750:Epithelial-Mesenchymal Transition; D017353:Gene Deletion; D018390:Gene Targeting; D049452:Green Fluorescent Proteins / Q000378:metabolism; D000090683:Hippo Signaling Pathway; D019426:Integrases / Q000378:metabolism; D018345:Mice, Knockout; D038081:Organogenesis; D010496:Pericardium / Q000166:cytology / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D039961:Semaphorins / Q000378:metabolism; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators; D025721:WT1 Proteins; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D010750:Phosphoproteins; D012097:Repressor Proteins; C530499:Sema 3D protein, mouse; D039961:Semaphorins; D020825:T-Box Domain Proteins; C420983:Tbx18 protein, mouse; D015534:Trans-Activators; D025721:WT1 Proteins; C000602896:WT1 protein, mouse; C517794:Wwtr1 protein, mouse; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; C045073:Cre recombinase; D019426:Integrases
keywords: Hippo signaling; Taz; Yap; epicardium; epithelial to mesenchymal transition (EMT); proepicardium