Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development
Crucial role of the small GTPase ARF6 in hepatic cord formation during liver development
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DOI：
10.1128/mcb.00298-06
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发表时间：
2006-08-01
影响因子：
5.3
通讯作者：
Kanaho, Yasunori
中科院分区：
文献类型：
--
作者：
Suzuki, Teruhiko;Kanai, Yoshiakira;Kanaho, Yasunori
哺乳动物小G蛋白ADP-核糖基化因子6（ARF 6）在多种细胞事件中发挥重要作用，包括内吞作用、肌动蛋白细胞骨架重组和磷酸肌醇代谢。然而，ARF 6的生理功能以前没有被研究过。在这里，我们描述了小鼠中ARF 6消融的结果，这在肝脏发育的背景下表现得最明显。来自ARF 6（-/-）胚胎的肝脏较小，由于妊娠中期肝细胞凋亡的发生，表现出细胞减少。然而，在细胞凋亡之前，观察到有缺陷的肝索形成;肝细胞在离开原始肝上皮片层和团块时异常迁移，而不是分散。与该观察结果一致，肝细胞生长因子/分散因子（HGF）诱导在胶原凝胶基质中体外培养的ARF 6（-/-）胎肝细胞形成肝索样结构的能力受损。最后，我们表明，内源性ARF 6在野生型胎肝细胞激活响应HGF刺激。这些结果提供了证据表明，ARF 6是一个重要的组成部分，在信号通路耦合肝细胞生长因子信号肝索形成。
The mammalian small GTPase ADP-ribosylation factor 6 (ARF6) plays important roles in a wide variety of cellular events, including endocytosis, actin cytoskeletal reorganization, and phosphoinositide metabolism. However, physiological functions for ARF6 have not previously been examined. Here, we described the consequence of ARF6 ablation in mice, which manifests most obviously in the context of liver development. Livers from ARF6(-/-) embryos are smaller and exhibit hypocellularity, due to the onset of midgestational liver cell apoptosis. Preceding the apoptosis, however, defective hepatic cord formation is observed; the liver cells migrate abnormally upon exiting the primordial hepatic epithelial sheet and clump rather than becoming dispersed. Consistent with this observation, the ability of hepatocyte growth factor/scatter factor (HGF) to induce hepatic cord-like structures from ARF6(-/-) fetal hepatocytes cultured in vitro in collagen gel matrix is impaired. Finally, we show that endogenous ARF6 in wild-type fetal hepatocytes is activated in response to HGF stimulation. These results provide evidence that ARF6 is an essential component in the signaling pathway coupling HGF signaling to hepatic cord formation.