The Mammalian Cos2 Homolog Kif7 Plays an Essential Role in Modulating Hh Signal Transduction during Development

被引:183
作者
Endoh-Yamagami, Setsu [1 ]
Evangelista, Marie [1 ]
Wilson, Deanna [1 ]
Wen, Xiaohui [1 ]
Theunissen, Jan-Willem [1 ]
Phamluong, Khanhky [1 ]
Davis, Matti [1 ]
Scales, Suzie J. [1 ]
Solloway, Mark J. [1 ]
de Sauvage, Frederic J. [1 ]
Peterson, Andrew S. [1 ]
机构
[1] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA
关键词
KINESIN-LIKE PROTEIN; HEDGEHOG SIGNAL; REPRESSOR FUNCTIONS; SONIC HEDGEHOG; DROSOPHILA; COSTAL2; ACTIVATOR; LOCALIZATION; DIVERGENCE; COMPLEX;
D O I
10.1016/j.cub.2009.06.046
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:1320 / 1326
页数:7
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