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


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.


  1. 1

    Watnick, T. & Germino, G. From cilia to cyst. Nat. Genet. 34, 355–356 (2003).

  2. 2

    Otto, E.A. et al. Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination. Nat. Genet. 34, 413–420 (2003).

  3. 3

    Mochizuki, T. et al. Cloning of inv, a gene that controls left/right asymmetry and kidney development. Nature 395, 177–181 (1998).

  4. 4

    Morgan, D. et al. Inversin, a novel gene in the vertebrate left-right axis pathway, is partially deleted in the inv mouse. Nat. Genet. 20, 149–156 (1998).

  5. 5

    Saadi-Kheddouci, S. et al. Early development of polycystic kidney disease in transgenic mice expressing an activated mutant of the beta-catenin gene. Oncogene 20, 5972–5981 (2001).

  6. 6

    Qian, C.N. et al. Cystic renal neoplasia following conditional inactivation of Apc in mouse renal tubular epithelium. J. Biol. Chem. 280, 3938–3945 (2004).

  7. 7

    Perantoni, A.O. Renal development: perspectives on a Wnt-dependent process. Semin. Cell. Dev. Biol. 14, 201–208 (2003).

  8. 8

    Guo, N., Hawkins, C. & Nathans, J. Frizzled6 controls hair patterning in mice. Proc. Natl. Acad. Sci. USA 101, 9277–9281 (2004).

  9. 9

    Moon, R.T., Bowerman, B., Boutros, M. & Perrimon, N. The promise and perils of Wnt signaling through beta-catenin. Science 296, 1644–1646 (2002).

  10. 10

    Wharton, K.A. Jr. Runnin' with the Dvl: proteins that associate with Dsh/Dvl and their significance to Wnt signal transduction. Dev. Biol. 253, 1–17 (2003).

  11. 11

    Veeman, M.T., Axelrod, J.D. & Moon, R.T. A second canon. Functions and mechanisms of beta-catenin-independent Wnt signaling. Dev. Cell 5, 367–377 (2003).

  12. 12

    Nelson, W.J. & Nusse, R. Convergence of Wnt, beta-catenin, and cadherin pathways. Science 303, 1483–1487 (2004).

  13. 13

    Zachariae, W. Destruction with a box: substrate recognition by the anaphase-promoting complex. Mol. Cell 13, 2–3 (2004).

  14. 14

    Morgan, D. et al. Expression analyses and interaction with the anaphase promoting complex protein Apc2 suggest a role for inversin in primary cilia and involvement in the cell cycle. Hum. Mol. Genet. 11, 3345–3350 (2002).

  15. 15

    Schwarz-Romond, T. et al. The ankyrin repeat protein Diversin recruits Casein kinase Iepsilon to the beta-catenin degradation complex and acts in both canonical Wnt and Wnt/JNK signaling. Genes Dev. 16, 2073–2084 (2002).

  16. 16

    Feiguin, F., Hannus, M., Mlodzik, M. & Eaton, S. The ankyrin repeat protein Diego mediates Frizzled-dependent planar polarization. Dev. Cell 1, 93–101 (2001).

  17. 17

    Stark, K., Vainio, S., Vassileva, G. & McMahon, A.P. Epithelial transformation of metanephric mesenchyme in the developing kidney regulated by Wnt-4. Nature 372, 679–683 (1994).

  18. 18

    Majumdar, A., Vainio, S., Kispert, A., McMahon, J. & McMahon, A.P. Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development 130, 3175–3185 (2003).

  19. 19

    Leung, T., Soll, I., Arnold, S.J., Kemler, R. & Driever, W. Direct binding of Lef1 to sites in the boz promoter may mediate pre-midblastula-transition activation of boz expression. Dev. Dyn. 228, 424–432 (2003).

  20. 20

    Imai, Y. et al. The homeobox genes vox and vent are redundant repressors of dorsal fates in zebrafish. Development 128, 2407–2420 (2001).

  21. 21

    Schneider, S., Steinbeisser, H., Warga, R.M. & Hausen, P. Beta-catenin translocation into nuclei demarcates the dorsalizing centers in frog and fish embryos. Mech. Dev. 57, 191–198 (1996).

  22. 22

    Das, G., Jenny, A., Klein, T.J., Eaton, S. & Mlodzik, M. Diego interacts with Prickle and Strabismus/Van Gogh to localize planar cell polarity complexes. Development 131, 4467–4476 (2004).

  23. 23

    Praetorius, H.A. & Spring, K.R. Bending the MDCK cell primary cilium increases intracellular calcium. J. Membr. Biol. 184, 71–79 (2001).

  24. 24

    Nauli, S.M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat. Genet. 33, 129–137 (2003).

  25. 25

    Liu, W. et al. Effect of flow and stretch on the [Ca2+]i response of principal and intercalated cells in cortical collecting duct. Am. J. Physiol. Renal Physiol. 285, F998–F1012 (2003).

  26. 26

    Friedberg, V. Studies on fetal urine secretion. Gynaecologia 140, 34–45 (1955).

  27. 27

    Kim, E. et al. The polycystic kidney disease 1 gene product modulates Wnt signaling. J. Biol. Chem. 274, 4947–4953 (1999).

  28. 28

    Nurnberger, J., Bacallao, R.L. & Phillips, C.L. Inversin forms a complex with catenins and N-cadherin in polarized epithelial cells. Mol. Biol. Cell 13, 3096–3106 (2002).

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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.

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Correspondence to Gerd Walz.

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The authors declare no competing financial interests.

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) doi:10.1038/ng1552

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