Wu Zhao-Qiu, Rowe R Grant, Lim Kim-Chew, Lin Yongshun, Willis Amanda, Tang Yi, Li Xiao-Yan, Nor Jacques E, Maillard Ivan, Weiss Stephen J
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.
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].
Nat Commun. 2014 Jun 4;5:3998. doi: 10.1038/ncomms4998.
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.
Notch1-类Delta样蛋白4（Dll4）信号通路通过调节内皮细胞（EC）靶点来控制血管发育，这些靶点可调节血管壁重塑和动静脉分化。在血管发育过程中调节Notch信号通路的分子效应器在很大程度上仍未明确。在此，我们证明转录抑制因子Snail1作为血管内皮生长因子（VEGF）诱导的Notch1信号通路和Dll4表达的调节因子。内皮细胞特异性Snail1功能缺失条件性敲除小鼠在子宫内死亡，伴有血管壁重塑缺陷，同时壁细胞附着减少以及动静脉分化紊乱。Snail1功能缺失条件性敲除胚胎进一步显示Notch1信号通路和Dll4表达上调，通过体内抑制γ-分泌酶活性可部分逆转这种上调，其中Dll4被确定为Snail1介导的转录抑制的直接靶点。这些结果证明了一个控制胚胎血管发育的Snail1-Dll4/Notch1轴。
