title: The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development.
abstract: 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. A kinesin-like protein, Costal2 (Cos2), plays a central role in the Hh pathway in flies. Knockdown of a zebrafish homolog of Cos2, Kif7, results in ectopic Hh signaling, suggesting that Kif7 acts primarily as a negative regulator of Hh signal transduction. 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. 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.
authors: Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
authors: Setsu
authors: S
authors: Endoh-Yamagami
authors: Marie
authors: M
authors: Evangelista
authors: Deanna
authors: D
authors: Wilson
authors: Xiaohui
authors: X
authors: Wen
authors: Jan-Willem
authors: JW
authors: Theunissen
authors: Khanhky
authors: K
authors: Phamluong
authors: Matti
authors: M
authors: Davis
authors: Suzie J
authors: SJ
authors: Scales
authors: Mark J
authors: MJ
authors: Solloway
authors: Frederic J
authors: FJ
authors: de Sauvage
authors: Andrew S
authors: AS
authors: Peterson
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D047108:Embryonic Development / Q000502:physiology*; D005838:Genotype; D049452:Green Fluorescent Proteins; D053823:Hedgehog Proteins / Q000378:metabolism*; D047468:Immunoprecipitation; D016547:Kinesins / Q000235:genetics* / Q000502:physiology; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D000074290:Zinc Finger Protein Gli3
chemical_list: D017931:DNA Primers; C465571:Gli3 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D009419:Nerve Tissue Proteins; D000074290:Zinc Finger Protein Gli3; D049452:Green Fluorescent Proteins; C543639:Kif7 protein, mouse; D016547:Kinesins