The Mammalian Cos2 Homolog Kif7 Plays an Essential Role in Modulating Hh Signal Transduction during Development
The Mammalian Cos2 Homolog Kif7 Plays an Essential Role in Modulating Hh Signal Transduction during Development
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DOI：
10.1016/j.cub.2009.06.046
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发表时间：
2009-08-11
期刊：
影响因子：
9.2
通讯作者：
Peterson, Andrew S.
中科院分区：
文献类型：
--
作者：
Endoh-Yamagami, Setsu;Evangelista, Marie;Peterson, Andrew S.
Hedgehog（Hh）信号通路调节从苍蝇到人类的动物的发育。虽然其框架是保守的，但已报道了途径组分的差异[1-4]。驱动蛋白样蛋白Costal 2（Cost）在果蝇的Hh途径中起核心作用[3，5]。敲低斑马鱼的Cost同源物Kif 7导致异位Hh信号传导，表明Kif 7主要作为Hh信号转导的负调节剂[6]。然而，对哺乳动物Kif 7和密切相关的Kif 27功能的体外分析得出结论，这两种蛋白质都不参与Hh信号传导[4]。使用Kif 7基因敲除小鼠，我们证明，小鼠Kif 7，像它的斑马鱼和果蝇的同源物，在Hh信号转导中发挥作用。我们发现，Kif 7积累在初级纤毛的末端在HH依赖的方式。我们还证明了Kif 7的要求，在有效的本地化Gli 3纤毛响应Hh和Gli 3的加工，其阻遏形式。这些结果表明，Kif 7的作用，在协调Hh信号转导的纤毛尖端，并防止Gli 3裂解成一个阻遏物的形式在Hh的存在下。
The Hedgehog (Hh) signaling pathway regulates development in animals ranging from flies to humans. Although its framework is conserved, differences in pathway components have been reported [1-4]. A kinesin-like protein, Costal2 (Cost), plays a central role in the Hh pathway in flies [3, 5]. Knockdown of a zebrafish homolog of Cost, Kif7, results in ectopic Hh signaling, suggesting that Kif7 acts primarily as a negative regulator of Hh signal transduction [6]. However, in vitro analysis of the function of mammalian Kif7 and the closely related Kif27 has led to the conclusion that neither protein has a role in Hh signaling [4]. Using Kif7 knockout mice, we demonstrate that mouse Kif7, like its zebrafish and Drosophila homologs, plays a role in transducing the Hh signal. We show that Kif7 accumulates at the distal tip of the primary cilia in a Hh-dependent manner. We also demonstrate a requirement for Kif7 in the efficient localization of Gli3 to cilia in response to Hh and for the processing of Gli3 to its repressor form. These results suggest a role for Kif7 in coordinating Hh signal transduction at the tip of cilia and preventing Gli3 cleavage into a repressor form in the presence of Hh.