Abstract
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.
Highlights
Notch and Angiopoietin-1 (Ang1)/Tie[2] pathways are crucial for vascular maturation and stability
The authors showed that Ang1-dependent potentiation of Delta-like ligand 4 (Dll4)/Notch signalling required Akt-mediated activation of b-catenin, which formed a complex with NICD18, providing in vitro evidence for an integrated network of endothelial pathways promoting vascular maturation and stability
Ang[1] has been shown to induce Dll[4] expression and Notch intracellular domain (NICD) signalling in vitro[18,34]; we investigated whether ERG mediates Ang1-dependent regulation of Notch signalling
Summary
Notch and Angiopoietin-1 (Ang1)/Tie[2] pathways are crucial for vascular maturation and stability. We show that ERG controls the balance between Notch ligands by driving Delta-like ligand 4 (Dll4) while repressing Jagged[1] (Jag1) expression In vivo, this regulation occurs selectively in the maturing plexus of the mouse developing retina, where Ang1/Tie[2] signalling is active. These two Notch ligands show distinct spatial expression patterns in the postnatal retina vasculature, with Dll[4] highly expressed in tip cells and present at the edge of the growing plexus, while Jag[1] expression is low/absent in tips cells but higher in adjacent stalk cells[8] The equilibrium between these two Notch ligands is required for the formation of fully functional and stable vascular networks. The authors showed that Ang1-dependent potentiation of Dll4/Notch signalling required Akt-mediated activation of b-catenin, which formed a complex with NICD18, providing in vitro evidence for an integrated network of endothelial pathways promoting vascular maturation and stability
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