Cystic renal diseases are caused by mutations of proteins that share a unique subcellular localization: the primary cilium of tubular epithelial cells1. Mutations of the ciliary protein inversin cause nephronophthisis type II, an autosomal recessive cystic kidney disease characterized by extensive renal cysts, situs inversus and renal failure2. Here we report that inversin acts as a molecular switch between different Wnt signaling cascades. Inversin inhibits the canonical Wnt pathway by targeting cytoplasmic dishevelled (Dsh or Dvl1) for degradation; concomitantly, it is required for convergent extension movements in gastrulating Xenopus laevis embryos and elongation of animal cap explants, both regulated by noncanonical Wnt signaling. In zebrafish, the structurally related switch molecule diversin ameliorates renal cysts caused by the depletion of inversin, implying that an inhibition of canonical Wnt signaling is required for normal renal development. Fluid flow increases inversin levels in ciliated tubular epithelial cells and seems to regulate this crucial switch between Wnt signaling pathways during renal development.
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We thank A. Schmitt for technical assistance; members of the laboratory of G.W. for discussions; E. Kim, K. Simons and S. Eaton for critically reading the manuscript; and P.A. Overbeek, P. Salinas, K. Wharton Jr., W. Birchmeier, H.J. Yost, S. Sokol, J. Axelrod and J. Nürnberger for providing materials. The work was supported by grants of the Deutsche Forschungsgemeinschaft.
The authors declare no competing financial interests.
Delayed nephron maturation and tubule differentiation in the (inv/inv) mouse. (PDF 678 kb)
Hair changes in inv/inv mice. (PDF 515 kb)
Inversin transcripts during early Xenopus development. (PDF 26 kb)
Comparison between mouse inversin and diversin. (PDF 50 kb)
Inversin shows the same binding behavior as Diego with respect to Prickle (Pk) and Strabismus (Stbm). (PDF 472 kb)
Primer sequences. (PDF 8 kb)
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Simons, M., Gloy, J., Ganner, A. et al. Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways. Nat Genet 37, 537–543 (2005). https://doi.org/10.1038/ng1552
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