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Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms

Nature Cell Biology volume 10, pages 70–76 (2008)Cite this article

A Corrigendum to this article was published on 01 April 2008

Abstract

Primary cilia are microtubule-based organelles involved in signal transduction and project from the surface of most vertebrate cells1. Proteins that can localize to the cilium, for example, Inversin and Bardet-Biedl syndrome (BBS) proteins, are implicated in both β-catenin-dependent and -independent Wnt signalling2,3,4. Given that Inversin and BBS proteins are found both at the cilium and elsewhere in the cell, the role of the cilium itself in Wnt signalling is not clear. Using three separate mutations that disrupt ciliogenesis (affecting Kif3a, Ift88 and Ofd1)5,6,7, we show in this study that the primary cilium restricts the activity of the canonical Wnt pathway in mouse embryos, primary fibroblasts, and embryonic stem cells. Interestingly, unciliated cells activate transcription only in response to Wnt stimulation, but do so much more robustly than ciliated cells. Loss of Kif3a, but not other ciliogenic genes, causes constitutive phosphorylation of Dishevelled (Dvl). Blocking the activity of casein kinase I (CKI) reverses this constitutive Dvl phosphorylation and abrogates pathway hyper-responsiveness. These results suggest that Kif3a restrains canonical Wnt signalling both by restricting the CKI-dependent phosphorylation of Dvl and through a separate ciliary mechanism. More generally, these findings reveal that, in contrast to its role in promoting Hedgehog (Hh) signalling, the cilium restrains canonical Wnt signalling.

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Figure 1: Loss of primary cilia increases responsiveness of the canonical Wnt pathway.
Figure 2: Mutation of Kif3a stabilizes β-catenin.
Figure 3: In the absence of Kif3a, Dvl was constitutively phosphorylated by CKI.
Figure 4: Wnt pathway components are present at cilia.
Figure 5: Ciliated and unciliated cells respond differently to Wnt stimulation.

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Acknowledgements

We thank S. Pleasure, B. Cheyette, and members of the Reiter lab for helpful discussions. Support for microscopy was provided by the NIH (P30 DK063720). This work was supported by funding from the NSF (V.S.), the CIRM (K.C.C.), the Sandler family, and the Burroughs Wellcome Fund.

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  1. Department of Biochemistry and Biophysics, Cardiovascular Research Institute, University of California, San Francisco, San Francisco, 94158-2324, California

    Kevin C. Corbit, Amy E. Shyer, William E. Dowdle, Julie Gaulden, Veena Singla & Jeremy F. Reiter

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  1. Kevin C. Corbit
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Correspondence to Jeremy F. Reiter.

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Corbit, K., Shyer, A., Dowdle, W. et al. Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat Cell Biol 10, 70–76 (2008). https://doi.org/10.1038/ncb1670

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