A Snail1/Notch1 signalling axis controls embryonic vascular development

Zhao-Qiu Wu, R. Grant Rowe, Kim-Chew Lim, Yongshun Lin, Amanda Willis, Yi Tang, Xiao-Yan Li, Jacques E. Nor, Ivan Maillard and Stephen J. Weiss ()
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Zhao-Qiu Wu: Division of Molecular Medicine and Genetics, Department of Internal Medicine
R. Grant Rowe: Division of Molecular Medicine and Genetics, Department of Internal Medicine
Kim-Chew Lim: Department of Cell and Developmental Biology
Yongshun Lin: Division of Molecular Medicine and Genetics, Department of Internal Medicine
Amanda Willis: Life Sciences Institute
Yi Tang: Division of Molecular Medicine and Genetics, Department of Internal Medicine
Xiao-Yan Li: Division of Molecular Medicine and Genetics, Department of Internal Medicine
Jacques E. Nor: Restorative Sciences, and Endodontics, University of Michigan
Ivan Maillard: Life Sciences Institute
Stephen J. Weiss: Division of Molecular Medicine and Genetics, Department of Internal Medicine

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms4998

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