The mammalian Cos2 homolog Kif7 plays an essential role in modulating Hh signal transduction during development.
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.
Endoh-Yamagami
Setsu
S
Department of Molecular Biology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, USA.
Evangelista
Marie
M
Wilson
Deanna
D
Wen
Xiaohui
X
Theunissen
Jan-Willem
JW
Phamluong
Khanhky
K
Davis
Matti
M
Scales
Suzie J
SJ
Solloway
Mark J
MJ
de Sauvage
Frederic J
FJ
Peterson
Andrew S
AS
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
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