Editors' ChoiceWnt signaling

Absence Makes the Wnt Go Stronger

Science Signaling  08 Jan 2008:
Vol. 1, Issue 1, pp. ec2
DOI: 10.1126/stke.11ec2

Wnts are secreted lipoproteins that are important in developmental processes. In the canonical Wnt pathway, Wnt3a signaling stabilizes β-catenin, which enters the nucleus and leads to expression of Wnt-target genes. Cilia are cellular projections that contain a central core of microtubules, and some proteins that are found in cilia, such as Inversin (see the commentary by He), mediate Wnt signaling. Corbit et al. investigated a possible role for cilia in the regulation of canonical Wnt signaling by generating mice and mouse embryonic fibroblasts (MEFs) deficient in Kif3a, which encodes a protein necessary for the generation of cilia. Reporter assays showed that Kif3a–/– MEFs responded more strongly to Wnt3a than did Kif3a+/– MEFs, whereas both cell types showed similar levels of basal activity. Western blotting assays showed that whereas Wnt3a treatment of Kif3a+/– MEFs resulted in the accumulation of β-catenin, Kif3a–/– MEFs showed a similar abundance of stabilized β-catenin even in the absence of Wnt3a. Wnt activation of Frizzled receptors results in the phosphorylation of Dishevelled (Dvl), which promotes stabilization of β-catenin. The authors showed by Western blotting that Dvl was constitutively phosphorylated in Kif3a–/– MEFs and that this was blocked by inhibition of casein kinase I (CKI), a kinase previously implicated in Dvl phosphorylation. Treatment with the CKI inhibitor also prevented the hyperresponsiveness of Kif3a–/– MEFs to treatment with Wnt3a, as assessed by reporter assays. Immunofluorescence microscopy demonstrated that some Wnt pathway components, including β-catenin, are present in cilia. This study suggests that cilia play a role in inhibiting canonical Wnt signaling, which may have implications for diseases associated with abnormal cilia, such as polycystic kidney disease.

K. C. Corbit, A. E. Shyer, W. E. Dowdle, J. Gaulden, V. Singla, J. F. Reiter, Kif3a constrains β-catenin-dependent Wnt signalling through dual ciliary and non-ciliary mechanisms. Nat. Cell Biol. 10, 70-76 (2008). [PubMed]

X. He, Cilia put a brake on Wnt signalling. Nat. Cell Biol. 10, 11-13 (2008). [PubMed]