Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants
Haploinsufficient lethality and formation of arteriovenous malformations in Notch pathway mutants
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DOI：
10.1101/gad.1239204
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发表时间：
2004-10-15
影响因子：
10.5
通讯作者：
Gridley, T
中科院分区：
文献类型：
--
作者：
Krebs, LT;Shutter, JR;Gridley, T
Notch信号通路对脊椎动物胚胎血管发育至关重要。本研究表明，编码DLL4配体的基因突变的杂合小鼠胚胎由于血管重构缺陷而表现出单倍体不足的致死率。我们还描述了Rbpsuh基因突变引起的胚胎血管缺陷，Rbpsuh基因编码Notch信号的主要转录介质。Rpbsuh功能的条件失活表明Notch激活在内皮细胞谱系中是必不可少的。Notch通路突变胚胎在新生血管的动脉规范中表现出缺陷，并发展为动静脉畸形。这些结果表明，小鼠胚胎血管重构对Dll4基因的剂量敏感，内皮细胞Notch的激活对胚胎血管重构至关重要。
The Notch signaling pathway is essential for embryonic vascular development in vertebrates. Here we show that mouse embryos heterozygous for a targeted mutation in the gene encoding the DLL4 ligand exhibit haploinsufficient lethality because of defects in vascular remodeling. We also describe vascular defects in embryos homozygous for a mutation in the Rbpsuh gene, which encodes the primary transcriptional mediator of Notch signaling. Conditional inactivation of Rpbsuh function demonstrates that Notch activation is essential in the endothelial cell lineage. Notch pathway mutant embryos exhibit defects in arterial specification of nascent blood vessels and develop arteriovenous malformations. These results demonstrate that vascular remodeling in the mouse embryo is sensitive to Dll4 gene dosage and that Notch activation in endothelial cells is essential for embryonic vascular remodeling.