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Inversin, the gene product mutated in nephronophthisis type II, functions as a molecular switch between Wnt signaling pathways

Abstract

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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Figure 1: Inversin inhibits canonical Wnt signaling.
Figure 2: Inversin interacts and colocalizes with Dvl1.
Figure 3: Inversin facilitates the degradation of Dvl1.
Figure 4: Inversin is required for convergent extension movements in X. laevis embryos.
Figure 5: Diversin rescues the renal cysts caused by inversin knockdown in zebrafish.

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Acknowledgements

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.

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Correspondence to Gerd Walz.

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Supplementary information

Supplementary Fig. 1

Delayed nephron maturation and tubule differentiation in the (inv/inv) mouse. (PDF 678 kb)

Supplementary Fig. 2

Hair changes in inv/inv mice. (PDF 515 kb)

Supplementary Fig. 3

Inversin transcripts during early Xenopus development. (PDF 26 kb)

Supplementary Fig. 4

Comparison between mouse inversin and diversin. (PDF 50 kb)

Supplementary Fig. 5

Inversin shows the same binding behavior as Diego with respect to Prickle (Pk) and Strabismus (Stbm). (PDF 472 kb)

Supplementary Table 1

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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