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


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 ?-catenin and is required for Ang1-dependent ?-catenin recruitment at the Dll4 locus. We propose that ERG coordinates Ang1, ?-catenin and Notch signalling to promote vascular stability.

SUBMITTER: Shah AV 

PROVIDER: S-EPMC5508205 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

Shah A V AV   Birdsey G M GM   Peghaire C C   Pitulescu M E ME   Dufton N P NP   Yang Y Y   Weinberg I I   Osuna Almagro L L   Payne L L   Mason J C JC   Gerhardt H H   Adams R H RH   Randi A M AM  

Nature communications 20170711


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  ...[more]

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