Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding

Abstract

Epithelial planar cell polarity (PCP) is evident in the cellular organization of many tissues in vertebrates and invertebrates1,2,3,4,5. In mammals, PCP signalling governs convergent extension during gastrulation and the organization of a wide variety of structures, including the orientation of body hair and sensory hair cells of the inner ear6,7. In Drosophila melanogaster, PCP is manifest in adult tissues, including ommatidial arrangement in the compound eye and hair orientation in wing cells1,2,4. PCP establishment requires the conserved Frizzled/Dishevelled PCP pathway1,2,3,4,5. Mutations in PCP-pathway-associated genes cause aberrant orientation of body hair or inner-ear sensory cells in mice6,7, or misorientation of ommatidia and wing hair in D. melanogaster1,2,4. Here we provide mechanistic insight into Frizzled/Dishevelled signalling regulation. We show that the ankyrin-repeat protein Diego binds directly to Dishevelled and promotes Frizzled signalling. Dishevelled can also be bound by the Frizzled PCP antagonist Prickle8. Strikingly, Diego and Prickle compete with one another for Dishevelled binding, thereby modulating Frizzled/Dishevelled activity and ensuring tight control over Frizzled PCP signalling.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: dgo is required in the R3 photoreceptor.
Figure 2: Genetic interactions of dgo with other PCP factors.
Figure 3: Dgo competes with Pk for Dsh binding.
Figure 4: Dgo and Pk compete with each other in vivo.
Figure 5: Model of how Dgo and the Pk–Stbm complex differentially affect Dsh and Fz PCP signalling in R3 and R4.

Similar content being viewed by others

References

  1. Adler, P.N. Planar signaling and morphogenesis in Drosophila. Dev. Cell 2, 525–535 (2002).

    Article  CAS  PubMed  Google Scholar 

  2. Mlodzik, M. Planar cell polarization: do the same mechanisms regulate Drosophila tissue polarity and vertebrate gastrulation? Trends Genet. 18, 564–571 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Keller, R. Shaping the vertebrate body plan by polarized embryonic cell movements. Science 298, 1950–1954 (2002).

    Article  CAS  PubMed  Google Scholar 

  4. Strutt, D. Frizzled signalling and cell polarisation in Drosophila and vertebrates. Development 130, 4501–4513 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Montcouquiol, M. et al. Identification of Vangl2 and Scrb1 as planar polarity genes in mammals. Nature 423, 173–177 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Tree, D.R. et al. Prickle mediates feedback amplification to generate asymmetric planar cell polarity signaling. Cell 109, 371–381 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Katanaev, V.L., Ponzielli, R., Semeriva, M. & Tomlinson, A. Trimeric G protein-dependent frizzled signaling in Drosophila. Cell 120, 111–122 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Strutt, D., Johnson, R., Cooper, K. & Bray, S. Asymmetric localization of frizzled and the determination of notch-dependent cell fate in the Drosophila eye. Curr. Biol. 12, 813–824 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Zheng, L., Zhang, J. & Carthew, R.W. frizzled regulates mirror-symmetric pattern formation in the Drosophila eye. Development 121, 3045–3055 (1995).

    CAS  PubMed  Google Scholar 

  12. Jenny, A., Darken, R.S., Wilson, P.A. & Mlodzik, M. Prickle and Strabismus form a functional complex to generate a correct axis during planar cell polarity signaling. EMBO J. 22, 4409–4420 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wolff, T. & Rubin, G.M. strabismus, a novel gene that regulates tissue polarity and cell fate decisions in Drosophila. Development 125, 1149–1159 (1998).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  16. Strutt, D.I. Asymmetric localization of frizzled and the establishment of cell polarity in the Drosophila wing. Mol. Cell 7, 367–375 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Bastock, R., Strutt, H. & Strutt, D. Strabismus is asymmetrically localised and binds to Prickle and Dishevelled during Drosophila planar polarity patterning. Development 130, 3007–3014 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Axelrod, J.D. Unipolar membrane association of Dishevelled mediates Frizzled planar cell polarity signaling. Genes Dev. 15, 1182–1187 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Boutros, M., Paricio, N., Strutt, D.I. & Mlodzik, M. Dishevelled activates JNK and discriminates between JNK pathways in planar polarity and wingless signaling. Cell 94, 109–118 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Strutt, D.I., Weber, U. & Mlodzik, M. The role of RhoA in tissue polarity and Frizzled signalling. Nature 387, 292–295 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Taylor, J., Abramova, N., Charlton, J. & Adler, P.N. Van Gogh: a new Drosophila tissue polarity gene. Genetics 150, 199–210 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Park, M. & Moon, R.T. The planar cell polarity gene stbm regulates cell behaviour and cell fate in vertebrate embryos. Nature Cell Biol. 4, 20–25 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Adler, P.N., Krasnow, R.E. & Liu, J. Tissue polarity points from cells that have higher Frizzled levels towards cells that have lower Frizzled levels. Curr. Biol. 7, 940–949 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Penton, A., Wodarz, A. & Nusse, R. A mutational analysis of dishevelled in Drosophila defines novel domains in the dishevelled protein as well as novel suppressing alleles of axin. Genetics 161, 747–762 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rothbacher, U. et al. Dishevelled phosphorylation, subcellular localization and multimerization regulate its role in early embryogenesis. EMBO J. 19, 1010–1022 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Wong, H.C. et al. Direct binding of the PDZ domain of Dishevelled to a conserved internal sequence in the C-terminal region of Frizzled. Mol. Cell 12, 1251–1260 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Carreira-Barbosa, F. et al. Prickle 1 regulates cell movements during gastrulation and neuronal migration in zebrafish. Development 130, 4037–4046 (2003).

    Article  CAS  PubMed  Google Scholar 

  29. Gubb, D. et al. The balance between isoforms of the prickle LIM domain protein is critical for planar polarity in Drosophila imaginal discs. Genes Dev. 13, 2315–2327 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Brand, A.H. & Perrimon, N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 (1993).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank D. Gubb, K. Basler, T. Wolff and the Bloomington stock center for fly strains, P. James for yeast strains, and J. Suriano and Z.-F. Du for technical help. We thank E. Wurmbach, R. Krauss and members of the Mlodzik laboratory for critically reading the manuscript. The work has been supported by NIH grant RO1 GM62917 to M.M. A.J. was supported in part by Swiss National Science Foundation grant 823A-64689.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Marek Mlodzik.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

Supplementary figures S1 and S2; supplementary table S1 (PDF 349 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jenny, A., Reynolds-Kenneally, J., Das, G. et al. Diego and Prickle regulate Frizzled planar cell polarity signalling by competing for Dishevelled binding. Nat Cell Biol 7, 691–697 (2005). https://doi.org/10.1038/ncb1271

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb1271

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing