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Crucial Role of the Small GTPase ARF6 in Hepatic Cord Formation during Liver Development

机译：小GTPase ARF6在肝发育过程中肝线形成中的关键作用

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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.
机译：哺乳动物小GTPase ADP-核糖基化因子6（ARF6）在多种细胞事件中发挥重要作用，包括胞吞作用，肌动蛋白细胞骨架重组和磷酸肌醇代谢。但是，ARF6的生理功能以前没有检查过。在这里，我们描述了 ARF6 消融在小鼠中的后果，这在肝脏发育的背景下最为明显。由于胚胎中期肝细胞凋亡的发生， ARF6 ？/？胚胎的肝脏较小，并显示出低细胞性。然而，在凋亡之前，观察到有缺陷的肝索形成。肝脏细胞在离开原始肝上皮片并结块而不是分散后异常迁移。与该观察结果一致，肝细胞生长因子/散射因子（HGF）诱导体外培养胶原蛋白的 ARF6 ？/？胎儿肝细胞的肝索样结构的能力凝胶基质受损。最后，我们表明野生型胎儿肝细胞中的内源性ARF6被激活响应HGF刺激。这些结果提供了证据，表明ARF6是将HGF信号传导至肝线形成的信号传导途径中的重要组成部分。

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