ETS factors regulate Vegf-dependent arterial specification

Dev Cell. 2013 Jul 15;26(1):45-58. doi: 10.1016/j.devcel.2013.06.007. Epub 2013 Jul 3.

Abstract

Vegf signaling specifies arterial fate during early vascular development by inducing the transcription of Delta-like 4 (Dll4), the earliest Notch ligand gene expressed in arterial precursor cells. Dll4 expression precedes that of Notch receptors in arteries, and factors that direct its arterial-specific expression are not known. To identify the transcriptional program that initiates arterial Dll4 expression, we characterized an arterial-specific and Vegf-responsive enhancer of Dll4. Our findings demonstrate that Notch signaling is not required for initiation of Dll4 expression in arteries and suggest that Notch instead functions as a maintenance factor. Importantly, we find that Vegf signaling activates MAP kinase (MAPK)-dependent E26 transformation-specific sequence (ETS) factors in the arterial endothelium to drive expression of Dll4 and Notch4. These findings identify a Vegf/MAPK-dependent transcriptional pathway that specifies arterial identity by activating Notch signaling components and illustrate how signaling cascades can modulate broadly expressed transcription factors to achieve tissue-specific transcriptional outputs.

Publication types

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

MeSH terms

  • Animals
  • Animals, Genetically Modified / embryology
  • Animals, Genetically Modified / metabolism
  • Aorta / metabolism
  • Aorta / physiology*
  • Binding Sites
  • Calcium-Binding Proteins
  • Endocardium / embryology
  • Endocardium / metabolism
  • Enhancer Elements, Genetic
  • Gene Expression Regulation, Developmental*
  • Green Fluorescent Proteins / genetics
  • Green Fluorescent Proteins / metabolism
  • Human Umbilical Vein Endothelial Cells / metabolism
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism
  • MAP Kinase Signaling System
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Organ Specificity
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Receptor, Notch4
  • Receptors, Notch / genetics
  • Receptors, Notch / metabolism
  • Trans-Activators / genetics
  • Trans-Activators / metabolism
  • Transcription, Genetic
  • Transcriptional Regulator ERG
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / metabolism*
  • Zebrafish / embryology
  • Zebrafish / genetics
  • Zebrafish / metabolism

Substances

  • Calcium-Binding Proteins
  • DLL4 protein, mouse
  • ERG protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NOTCH4 protein, human
  • Proto-Oncogene Proteins
  • Receptor, Notch4
  • Receptors, Notch
  • Trans-Activators
  • Transcriptional Regulator ERG
  • Vascular Endothelial Growth Factor A
  • vascular endothelial growth factor A, mouse
  • Green Fluorescent Proteins