ER71 specifies Flk-1+ hemangiogenic mesoderm by inhibiting cardiac mesoderm and Wnt signaling

Blood. 2012 Apr 5;119(14):3295-305. doi: 10.1182/blood-2012-01-403766. Epub 2012 Feb 17.


Two distinct types of Flk-1(+) mesoderm, hemangiogenic and cardiogenic, are thought to contribute to blood, vessel, and cardiac cell lineages. However, our understanding of how Flk-1(+) mesoderm is specified is currently limited. In the present study, we investigated whether ER71, an Ets transcription factor essential for hematopoietic and endothelial cell lineage development, could modulate the hemangiogenic or cardiogenic outcome of the Flk-1(+) mesoderm. We show that Flk-1(+) mesoderm can be divided into Flk-1(+)PDGFRα(-) hemangiogenic and Flk-1(+)PDGFRα(+) cardiogenic mesoderm. ER71-deficient embryonic stem cells produced only the Flk-1(+)PDGFRα(+) cardiogenic mesoderm, which generated SMCs and cardiomyocytes. Enforced ER71 expression in the wild-type embryonic stem cells skewed toward the Flk-1(+)PDGFRα(-) mesoderm formation, which generated hematopoietic and endothelial cells. Whereas hematopoietic and endothelial cell genes were positively regulated by ER71, cardiac and Wnt signaling pathway genes were negatively regulated by ER71. We show that ER71 could inhibit Wnt signaling in VE-cadherin-independent as well as VE-cadherin-dependent VE-cadherin/β-catenin/Flk-1 complex formation. Enforced β-catenin could rescue cardiogenic mesoderm in the context of ER71 overexpression. In contrast, ER71-deficient Flk-1(+) mesoderm displayed enhanced Wnt signaling, which was reduced by ER71 re-introduction. We provide the molecular basis for the antagonistic relationship between hemangiogenic and cardiogenic mesoderm specification by ER71 and Wnt signaling.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Cadherins / genetics
  • Cadherins / metabolism
  • Cell Line
  • Cluster Analysis
  • Embryonic Stem Cells / metabolism
  • Endothelial Cells / metabolism
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Hematopoietic Stem Cells / metabolism
  • Mesoderm / metabolism*
  • Mice
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Smooth Muscle / metabolism
  • Neovascularization, Physiologic* / genetics
  • Protein Binding
  • Receptor, Platelet-Derived Growth Factor alpha / metabolism
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism*
  • Wnt Signaling Pathway*
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • Antigens, CD
  • Cadherins
  • ER71 protein, mouse
  • Transcription Factors
  • beta Catenin
  • cadherin 5
  • Receptor, Platelet-Derived Growth Factor alpha
  • Vascular Endothelial Growth Factor Receptor-2