title: A Snail1/Notch1 signalling axis controls embryonic vascular development.
abstract: Notch1-Delta-like 4 (Dll4) signalling controls vascular development by regulating endothelial cell (EC) targets that modulate vessel wall remodelling and arterial-venous specification. The molecular effectors that modulate Notch signalling during vascular development remain largely undefined. Here we demonstrate that the transcriptional repressor, Snail1, acts as a VEGF-induced regulator of Notch1 signalling and Dll4 expression. EC-specific Snail1 loss-of-function conditional knockout mice die in utero with defects in vessel wall remodelling in association with losses in mural cell investment and disruptions in arterial-venous specification. Snail1 loss-of-function conditional knockout embryos further display upregulated Notch1 signalling and Dll4 expression that is partially reversed by inhibiting γ-secretase activity in vivo with Dll4 identified as a direct target of Snail1-mediated transcriptional repression. These results document a Snail1-Dll4/Notch1 axis that controls embryonic vascular development.
authors.affiliation: 1] Division of Molecular Medicine and Genetics, Department of Internal Medicine, Ann Arbor, Michigan 48109, USA [2] Life Sciences Institute, Ann Arbor, Michigan 48109, USA.
authors.forename: Zhao-Qiu
authors.initials: ZQ
authors.lastname: Wu
authors.affiliation: 1] Division of Molecular Medicine and Genetics, Department of Internal Medicine, Ann Arbor, Michigan 48109, USA [2] Life Sciences Institute, Ann Arbor, Michigan 48109, USA [3].
authors.forename: R Grant
authors.initials: RG
authors.lastname: Rowe
authors.affiliation: Department of Cell and Developmental Biology, Ann Arbor, Michigan 48109, USA.
authors.forename: Kim-Chew
authors.initials: KC
authors.lastname: Lim
authors.affiliation: 1] Division of Molecular Medicine and Genetics, Department of Internal Medicine, Ann Arbor, Michigan 48109, USA [2] Life Sciences Institute, Ann Arbor, Michigan 48109, USA [3].
authors.forename: Yongshun
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Life Sciences Institute, Ann Arbor, Michigan 48109, USA.
authors.forename: Amanda
authors.initials: A
authors.lastname: Willis
authors.affiliation: 1] Division of Molecular Medicine and Genetics, Department of Internal Medicine, Ann Arbor, Michigan 48109, USA [2] Life Sciences Institute, Ann Arbor, Michigan 48109, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Tang
authors.affiliation: 1] Division of Molecular Medicine and Genetics, Department of Internal Medicine, Ann Arbor, Michigan 48109, USA [2] Life Sciences Institute, Ann Arbor, Michigan 48109, USA.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Li
authors.affiliation: Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Nor
authors.affiliation: 1] Life Sciences Institute, Ann Arbor, Michigan 48109, USA [2] Department of Cell and Developmental Biology, Ann Arbor, Michigan 48109, USA [3] Division of Hematology-Oncology, Department of Medicine, Ann Arbor, Michigan 48109, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Maillard
authors.affiliation: 1] Division of Molecular Medicine and Genetics, Department of Internal Medicine, Ann Arbor, Michigan 48109, USA [2] Life Sciences Institute, Ann Arbor, Michigan 48109, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Weiss
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001808:Blood Vessels / Q000196:embryology*; D002135:Calcium-Binding Proteins; D042783:Endothelial Cells / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D025461:Feedback, Physiological; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D066253:Vascular Remodeling / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse