Nature Communications
Nature Communications
5 years ago

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

The endothelial transcription factor ERG mediates Angiopoietin-1-dependent control of Notch signalling and vascular stability
A. V. Shah, R. H. Adams, L. Payne, Y. Yang, A. M. Randi, J. C. Mason, C. Peghaire, L. Osuna Almagro, I. Weinberg, M. E. Pitulescu, H. Gerhardt, G. M. Birdsey, N. P. Dufton
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.

Publisher URL: https://www.nature.com/articles/ncomms16002

DOI: 10.1038/ncomms16002

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