Mouse Fbw7/Sel-10/Cdc4 is required for Notch degradation during vascular development
Mouse Fbw7/Sel-10/Cdc4 is required for Notch degradation during vascular development
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DOI：
10.1074/jbc.m312337200
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发表时间：
2004-03-05
影响因子：
4.8
通讯作者：
Nakayama, KI
中科院分区：
文献类型：
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作者：
Tsunematsu, R;Nakayama, K;Nakayama, KI
哺乳动物Fbw7（也称为Sel-10、hCdc4或hAgo）是SCF （Skp1-Cul1-F-box蛋白- rbx1）型泛素连接酶的F-box蛋白组分，小鼠Fbw7在胚胎内皮细胞谱系中显著表达。我们培育了Fbw7缺失的小鼠，发现胚胎在胚胎期10.5-11.5天在子宫内死亡，血管发育明显异常。脑和卵黄囊血管重构受损，主干静脉未形成。体外培养的Fbw7（-/-）胚胎的主动脉旁胸膜外植体也表现出血管网络形成的损害。Notch4是原癌基因Int3和Notch的内皮细胞特异性哺乳动物亚型的产物，在Fbw7（-/-）胚胎中积累，导致Hey1表达增加，Hey1编码Notch信号下游的转录抑制因子，参与血管发育。在Fbw7（-/-）胚胎中，Notch1、-2、-3或cyclin E的表达不受影响。因此，哺乳动物Fbw7似乎在Notch4-Hey1通路的负调控中发挥了不可或缺的作用，并且是血管发育所必需的。
Mammalian Fbw7 (also known as Sel-10, hCdc4, or hAgo) is the F-box protein component of an SCF (Skp1-Cul1-F-box protein-Rbx1)-type ubiquitin ligase, and the mouse Fbw7 is expressed prominently in the endothelial cell lineage of embryos. We generated mice deficient in Fbw7 and found that the embryos died in utero at embryonic day 10.5-11.5, manifesting marked abnormalities in vascular development. Vascular remodeling was impaired in the brain and yolk sac, and the major trunk veins were not formed. In vitro para-aortic splanchnopleural explant cultures from Fbw7(-/-) embryos also manifested an impairment of vascular network formation. Notch4, which is the product of the proto-oncogene Int3 and an endothelial cell-specific mammalian isoform of Notch, accumulated in Fbw7(-/-) embryos, resulting in an increased expression of Hey1, which encodes a transcriptional repressor that acts downstream of Notch signaling and is implicated in vascular development. Expression of Notch1, -2, or -3 or of cyclin E was unaffected in Fbw7(-/-) embryos. Mammalian Fbw7 thus appears to play an indispensable role in negative regulation of the Notch4-Hey1 pathway and is required for vascular development.