Hippo Signaling Mediators Yap and Taz Are Required in the Epicardium for Coronary Vasculature Development

Cell Rep. 2016 May 17;15(7):1384-1393. doi: 10.1016/j.celrep.2016.04.027. Epub 2016 May 5.

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.

Keywords: Hippo signaling; Taz; Yap; epicardium; epithelial to mesenchymal transition (EMT); proepicardium.

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Cycle Proteins
  • Cell Differentiation
  • Cell Movement
  • Cell Proliferation
  • Coronary Vessels / cytology
  • Coronary Vessels / embryology*
  • Coronary Vessels / metabolism*
  • Embryo Loss / metabolism
  • Embryo Loss / pathology
  • Embryonic Development
  • Endothelial Cells / cytology
  • Epithelial-Mesenchymal Transition
  • Gene Deletion
  • Gene Targeting
  • Green Fluorescent Proteins / metabolism
  • Integrases / metabolism
  • Mice, Knockout
  • Organogenesis*
  • Pericardium / cytology
  • Pericardium / metabolism*
  • Phosphoproteins / metabolism*
  • Promoter Regions, Genetic / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Semaphorins / metabolism
  • Signal Transduction*
  • T-Box Domain Proteins / genetics
  • T-Box Domain Proteins / metabolism
  • Trans-Activators
  • WT1 Proteins

Substances

  • Adaptor Proteins, Signal Transducing
  • Cell Cycle Proteins
  • Phosphoproteins
  • Repressor Proteins
  • Sema 3D protein, mouse
  • Semaphorins
  • T-Box Domain Proteins
  • Tbx18 protein, mouse
  • Trans-Activators
  • WT1 Proteins
  • WT1 protein, mouse
  • Wwtr1 protein, mouse
  • Yap1 protein, mouse
  • Green Fluorescent Proteins
  • Hippo protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cre recombinase
  • Integrases