The endothelial transcription factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability

نویسندگان

  • A V Shah
  • G M Birdsey
  • C Peghaire
  • M E Pitulescu
  • N P Dufton
  • Y Yang
  • I Weinberg
  • L Osuna Almagro
  • L Payne
  • J C Mason
  • H Gerhardt
  • R H Adams
  • A M Randi
چکیده

Notch and Angiopoietin-1 (Ang1)/Tie2 pathways are crucial for vascular maturation and stability. Here we identify the transcription factor ERG as a key regulator of endothelial Notch signalling. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged1 (Jag1) expression. In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie2 signalling is active. We find that ERG mediates Ang1-dependent regulation of Notch ligands and is required for the stabilizing effects of Ang1 in vivo. We show that Ang1 induces ERG phosphorylation in a phosphoinositide 3-kinase (PI3K)/Akt-dependent manner, resulting in ERG enrichment at Dll4 promoter and multiple enhancers. Finally, we demonstrate that ERG directly interacts with Notch intracellular domain (NICD) and β-catenin and is required for Ang1-dependent β-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, β-catenin and Notch signalling to promote vascular stability.

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عنوان ژورنال:

دوره 8  شماره 

صفحات  -

تاریخ انتشار 2017