Vertebrate Smoothened functions at the primary cilium

KC Corbit, P Aanstad, V Singla, AR Norman… - Nature, 2005 - nature.com
KC Corbit, P Aanstad, V Singla, AR Norman, DYR Stainier, JF Reiter
Nature, 2005nature.com
The unanticipated involvement of several intraflagellar transport proteins in the mammalian
Hedgehog (Hh) pathway has hinted at a functional connection between cilia and Hh signal
transduction,. Here we show that mammalian Smoothened (Smo), a seven-transmembrane
protein essential for Hh signalling, is expressed on the primary cilium. This ciliary expression
is regulated by Hh pathway activity; Sonic hedgehog or activating mutations in Smo promote
ciliary localization, whereas the Smo antagonist cyclopamine inhibits ciliary localization. The …
Abstract
The unanticipated involvement of several intraflagellar transport proteins in the mammalian Hedgehog (Hh) pathway has hinted at a functional connection between cilia and Hh signal transduction,. Here we show that mammalian Smoothened (Smo), a seven-transmembrane protein essential for Hh signalling, is expressed on the primary cilium. This ciliary expression is regulated by Hh pathway activity; Sonic hedgehog or activating mutations in Smo promote ciliary localization, whereas the Smo antagonist cyclopamine inhibits ciliary localization. The translocation of Smo to primary cilia depends upon a conserved hydrophobic and basic residue sequence homologous to a domain previously shown to be required for the ciliary localization of seven-transmembrane proteins in Caenorhabditis elegans. Mutation of this domain not only prevents ciliary localization but also eliminates Smo activity both in cultured cells and in zebrafish embryos. Thus, Hh-dependent translocation to cilia is essential for Smo activity, suggesting that Smo acts at the primary cilium.
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