Importance of endothelial Hey1 expression for thoracic great vessel development and its distal enhancer for Notch-dependent endothelial transcription.
Thoracic great vessels such as the aorta and subclavian arteries are formed through dynamic remodeling of embryonic pharyngeal arch arteries (PAAs). Previous work has shown that loss of a basic helix-loop-helix transcription factor Hey1 in mice causes abnormal fourth PAA development and lethal great vessel anomalies resembling congenital malformations in humans. However, how Hey1 mediates vascular formation remains unclear. In this study, we revealed that Hey1 in vascular endothelial cells, but not in smooth muscle cells, played essential roles for PAA development and great vessel morphogenesis in mouse embryos. Tek-Cre-mediated Hey1 deletion in endothelial cells affected endothelial tube formation and smooth muscle differentiation in embryonic fourth PAAs and resulted in interruption of the aortic arch and other great vessel malformations. Cell specificity and signal responsiveness of Hey1 expression were controlled through multiple cis-regulatory regions. We found two distal genomic regions that had enhancer activity in endothelial cells and in the pharyngeal epithelium and somites, respectively. The novel endothelial enhancer was conserved across species and was specific to large-caliber arteries. Its transcriptional activity was regulated by Notch signaling in vitro and in vivo, but not by ALK1 signaling and other transcription factors implicated in endothelial cell specificity. The distal endothelial enhancer was not essential for basal Hey1 expression in mouse embryos but may likely serve for Notch-dependent transcriptional control in endothelial cells together with the proximal regulatory region. These findings help in understanding the significance and regulation of endothelial Hey1 as a mediator of multiple signaling pathways in embryonic vascular formation.
['Watanabe|Yusuke|Y|', 'Seya|Daiki|D|', 'Ihara|Dai|D|', 'Ishii|Shuhei|S|', 'Uemoto|Taiki|T|', 'Kubo|Atsushi|A|', 'Arai|Yuji|Y|', 'Isomoto|Yoshie|Y|', 'Nakano|Atsushi|A|', 'Abe|Takaya|T|', 'Shigeta|Mayo|M|', 'Kawamura|Teruhisa|T|', 'Saito|Yoshihiko|Y|', 'Ogura|Toshihiko|T|', 'Nakagawa|Osamu|O|']
D000818:Animals D001158:Arteries D001934:Branchial Region D018797:Cell Cycle Proteins D002454:Cell Differentiation D004622:Embryo, Mammalian D004727:Endothelium D005260:Female D006801:Humans D051379:Mice D018345:Mice, Knockout D009024:Morphogenesis D032389:Myocytes, Smooth Muscle D017394:RNA, Guide D051880:Receptors, Notch D012045:Regulatory Sequences, Nucleic Acid D015398:Signal Transduction D015533:Transcriptional Activation
Hey1 development pharyngeal arch artery endothelial cell great vessel morphogenesis embryo Notch signaling cardiovascular disease gene knockout great vessel morphogenesis Hey1 transcription regulation