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.

  • Article
  • Published:

A new nuclear component of the Wnt signalling pathway

Nature Cell Biology volume 4, pages 367–373 (2002)Cite this article

Abstract

The Wnt signalling pathway is pivotal in normal and malignant development. A key effector is Armadillo (Arm)/β-catenin, which functions with TCF to transcribe Wnt target-genes. Here, we report the discovery of pygopus (pygo), whose mutant phenotypes specifically mimic loss-of-Wingless (Wg) signalling. pygo is required for dTCF-mediated transcription, but not for Wg-induced stabilization of Arm. Pygo is a nuclear protein that is found in a complex with Arm in vivo. Humans possess two Pygo proteins, both of which are required for TCF-mediated transcription in colorectal cancer cells. The presence of a PHD domain implicates Pygo proteins in a chromatin-related function, and we propose that they mediate chromatin access to TCF or Arm/β-catenin.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: The pygo mutant phenotypes mimic loss-of-Wg signalling.
Figure 2: pygo is required for the transcription of embryonic Wg target-genes.
Figure 3: pygo controls a Wg target-gene in imaginal discs.
Figure 4: Drosophila and human pygo genes.
Figure 5: Pygo is localized to the nucleus and is found in a complex with Arm.
Figure 6: Function of human Pygo in colorectal cancer cells.

Similar content being viewed by others

Accession codes

Accessions

Protein Data Bank

References

  1. Cadigan, K. M. & Nusse, R. Wnt signaling: a common theme in animal development. Genes Dev. 11, 3286–3305 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Perrimon, N. The genetic basis of patterned baldness in Drosophila. Cell 76, 781–784 (1994).

    Article  CAS  PubMed  Google Scholar 

  3. Miller, J. R. & Moon, R. T. Signal transduction through β-catenin and specification of cell fate during embryogenesis. Genes Dev. 10, 2527–2539 (1996).

    Article  CAS  PubMed  Google Scholar 

  4. Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).

    CAS  PubMed  Google Scholar 

  5. Bienz, M. & Clevers, H. Linking colorectal cancer to Wnt signaling. Cell 103, 311–320 (2000).

    Article  CAS  PubMed  Google Scholar 

  6. Morin, P. J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).

    Article  CAS  PubMed  Google Scholar 

  7. Freeman, M. & Bienz, M. EGF receptor/Rolled MAP kinase signalling protects cells against activated Armadillo in the Drosophila eye. EMBO Rep. 2, 157–162 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Baker, N. E. Embryonic and imaginal requirements for wingless, a segment-polarity gene in Drosophila. Dev. Biol. 125, 96–108 (1988).

    Article  CAS  PubMed  Google Scholar 

  9. Peifer, M., Rauskolb, C., Williams, M., Riggleman, B. & Wieschaus, E. The segment polarity gene armadillo interacts with the Wingless signaling pathway in both embryonic and adult pattern formation. Development 111, 1029–1043 (1991).

    CAS  PubMed  Google Scholar 

  10. van de Wetering, M. et al. Armadillo coactivates transcription driven by the product of the Drosophila segment polarity gene dTCF. Cell 88, 789–799 (1997).

    Article  CAS  PubMed  Google Scholar 

  11. Brunner, E., Peter, O., Schweizer, L. & Basler, K. Pangolin encodes a Lef-1 homologue that acts downstream of Armadillo to transduce the Wingless signal in Drosophila. Nature 385, 829–833 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Phillips, R. G. & Whittle, J. R. Wingless expression mediates determination of peripheral nervous system elements in late stages of Drosophila wing disc development. Development 118, 427–438 (1993).

    CAS  PubMed  Google Scholar 

  13. Couso, J. P., Bishop, S. A. & Martinez Arias, A. The Wingless signalling pathway and the patterning of the wing margin in Drosophila. Development 120, 621–636 (1994).

    CAS  PubMed  Google Scholar 

  14. Neumann, C. & Cohen, S. Morphogens and pattern formation. Bioessays 19, 721–729 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Blair, S. S. & Ralston, A. Smoothened-mediated Hedgehog signalling is required for the maintenance of the anterior-posterior lineage restriction in the developing wing of Drosophila. Development 124, 4053–4063 (1997).

    CAS  PubMed  Google Scholar 

  16. Rodriguez, I. & Basler, K. Control of compartmental affinity boundaries by Hedgehog. Nature 389, 614–618 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Sturtevant, M. A. & Bier, E. Analysis of the genetic hierarchy guiding wing vein development in Drosophila. Development 121, 785–801 (1995).

    CAS  PubMed  Google Scholar 

  18. Freeman, M. Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87, 651–660 (1996).

    Article  CAS  PubMed  Google Scholar 

  19. Dominguez, M. & Hafen, E. Hedgehog directly controls initiation and propagation of retinal differentiation in the Drosophila eye. Genes Dev. 11, 3254–3264 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Pai, L. M., Orsulic, S., Bejsovec, A. & Peifer, M. Negative regulation of Armadillo, a Wingless effector in Drosophila. Development 124, 2255–2266 (1997).

    CAS  PubMed  Google Scholar 

  21. Yoffe, K. B., Manoukian, A. S., Wilder, E. L., Brand, A. H. & Perrimon, N. Evidence for engrailed-independent wingless autoregulation in Drosophila. Dev. Biol. 170, 636–650 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Bejsovec, A. & Martinez Arias, A. Roles of wingless in patterning the larval epidermis of Drosophila. Development 113, 471–485 (1991).

    CAS  PubMed  Google Scholar 

  23. Thüringer, F., Cohen, S. M. & Bienz, M. Dissection of an indiret autoregulatory response of a homeotic Drosophila gene. EMBO J. 12, 2419–2430 (1993).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Riese, J. et al. LEF-1, a nuclear factor coordinating signaling inputs from wingless and decapentaplegic. Cell 88, 777–787 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Yu, X., Hoppler, S., Eresh, S. & Bienz, M. Decapentaplegic, a target gene of the wingless signalling pathway in the Drosophila midgut. Development 122, 849–858 (1996).

    CAS  PubMed  Google Scholar 

  26. Zecca, M., Basler, K. & Struhl, G. Direct and long-range action of a wingless morphogen gradient. Cell 87, 833–844 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Peifer, M., Sweeton, D., Casey, M. & Wieschaus, E. Wingless signal and Zeste-white 3 kinase trigger opposing changes in the intracellular distribution of Armadillo. Development 120, 369–380 (1994).

    CAS  PubMed  Google Scholar 

  28. Rulifson, E. J., Micchelli, C. A., Axelrod, J. D., Perrimon, N. & Blair, S. S. Wingless refines its own expression domain on the Drosophila wing margin. Nature 384, 72–74 (1996).

    Article  CAS  PubMed  Google Scholar 

  29. Aasland, R., Gibson, T. J. & Stewart, A. F. The PHD finger: implications for chromatin-mediated transcriptional regulation. Trends Biochem. Sci. 20, 56–59 (1995).

    Article  CAS  PubMed  Google Scholar 

  30. Pascual, J., Martinez-Yamout, M., Dyson, H. J. & Wright, P. E. Structure of the PHD zinc finger from human Williams-Beuren syndrome transcription factor. J. Mol. Biol. 304, 723–729 (2000).

    Article  PubMed  Google Scholar 

  31. Capili, A. D., Schultz, D. C., Rauscher, I. F. & Borden, K. L. Solution structure of the PHD domain from the KAP-1 corepressor: structural determinants for PHD, RING and LIM zinc-binding domains. EMBO J. 20, 165–177 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Jacobson, S. & Pillus, L. Modifying chromatin and concepts of cancer. Curr. Opin. Genet. Dev. 9, 175–184 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Roose, J. et al. The Xenopus Wnt effector XTcf-3 interacts with Groucho-related transcriptional repressors. Nature 395, 608–612 (1998).

    Article  CAS  PubMed  Google Scholar 

  34. Waltzer, L. & Bienz, M. Drosophila CBP represses the transcription factor TCF to antagonize Wingless signalling. Nature 395, 521–525 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    Article  CAS  PubMed  Google Scholar 

  36. Korinek, V. et al. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC-/- colon carcinoma. Science 275, 1784–1787 (1997).

    Article  CAS  PubMed  Google Scholar 

  37. Roose, J. & Clevers, H. TCF transcription factors: molecular switches in carcinogenesis. Biochim. Biophys. Acta 1424, M23–M37 (1999).

  38. Levanon, D. et al. Transcriptional repression by AML1 and LEF-1 is mediated by the TLE/Groucho corepressors. Proc. Natl Acad. Sci. USA 95, 11590–11595 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brannon, M., Brown, J. D., Bates, R., Kimelman, D. & Moon, R. T. XCtBP is a XTcf-3 co-repressor with roles throughout Xenopus development. Development 126, 3159–3170 (1999).

    CAS  PubMed  Google Scholar 

  40. Hecht, A., Vleminckx, K., Stemmler, M. P., van Roy, F. & Kemler, R. The p300/CBP acetyltransferases function as transcriptional coactivators of β-catenin in vertebrates. EMBO J. 19, 1839–1850 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Takemaru, K. I. & Moon, R. T. The transcriptional coactivator CBP interacts with β-catenin to activate gene expression. J. Cell Biol. 149, 249–254 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Barker, N. et al. The chromatin remodelling factor Brg-1 interacts with β-catenin to promote target gene activation. EMBO J. 20, 4935–4943 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tutter, A. V., Fryer, C. J. & Jones, K. A. Chromatin-specific regulation of LEF-1-β-catenin transcription activation and inhibition in vitro. Genes Dev. 15, 3342–3354 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Daniels, D. L., Eklof Spink, K. & Weis, W. I. β-catenin: molecular plasticity and drug design. Trends Biochem. Sci. 26, 672–678 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Hsu, S. C., Galceran, J. & Grosschedl, R. Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with β-catenin. Mol. Cell. Biol. 18, 4807–4818 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. von Kries, J. P. et al. Hot spots in β-catenin for interactions with LEF-1, conductin and APC. Nature Struct. Biol. 7, 800–807 (2000).

    Article  CAS  PubMed  Google Scholar 

  47. Yokoya, F., Imamoto, N., Tachibana, T. & Yoneda, Y. β-catenin can be transported into the nucleus in a Ran-unassisted manner. Mol. Biol. Cell 10, 1119–1131 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wiechens, N. & Fagotto, F. CRM1- and Ran-independent nuclear export of β-catenin. Curr. Biol. 11, 18–27 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Tolwinski, N. S. & Wieschaus, E. Armadillo nuclear import is regulated by cytoplasmic anchor Axin and nuclear anchor dTCF/Pan. Development 128, 2107–2117 (2001).

    CAS  PubMed  Google Scholar 

  50. Eklof Spink, K., Fridman, S. G. & Weis, W. I. Molecular mechanisms of β-catenin recognition by adenomatous polyposis coli revealed by the structure of an APC–β-catenin complex. EMBO J. 20, 6203–6212 (2001).

    Article  CAS  PubMed  Google Scholar 

  51. Sanson, B., White, P. & Vincent, J. P. Uncoupling cadherin-based adhesion from wingless signalling in Drosophila. Nature 383, 627–630 (1996).

    Article  PubMed  Google Scholar 

  52. Neumann, C. J. & Cohen, S. M. Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing. Development 124, 871–880 (1997).

    CAS  PubMed  Google Scholar 

  53. Van de Wetering, M., Castrop, J., Korinek, V. & Clevers, H. Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties. Mol. Cell. Biol. 16, 745–752 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. McCartney, B. M. et al. Drosophila APC2 and Armadillo participate in tethering mitotic spindles to cortical actin. Nature Cell Biol. 3, 933–938 (2001).

    Article  CAS  PubMed  Google Scholar 

  55. Rosin-Arbesfeld, R., Townsley, F. & Bienz, M. The APC tumour suppressor has a nuclear export function. Nature 406, 1009–1012 (2000).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to thank A. Baonza, M. van Beest, C. Murawsky and M. Frasch for antibodies, B. Nichols and S. Munro for RNA oligomers, H. Clevers and S. Munro for plasmids, A. Baonza for technical advice on wing discs, and H. Pelham, M. Freeman and A. Travers for critical comments on the manuscript. Thanks also to R. Nusse for suggesting the name Pygopus, a legless and scaly lizard, reminiscent of the pygopus mutant phenotype. R.R.-A. is supported by an EMBO Long-term fellowship.

Author information

Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Hills Road, Cambridge, CB2 2QH, UK

    Barry Thompson, Fiona Townsley, Rina Rosin-Arbesfeld, Hannah Musisi & Mariann Bienz

Authors
  1. Barry Thompson
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fiona Townsley
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rina Rosin-Arbesfeld
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hannah Musisi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariann Bienz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mariann Bienz.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Figure S1.Suppression of the Armadillo* phenotype by pygo.

Figure S2. Embryonic expression of pygo. (PDF 471 kb)

Figure S3. Armadillo is less nuclear in pygo mutant embryos.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Thompson, B., Townsley, F., Rosin-Arbesfeld, R. et al. A new nuclear component of the Wnt signalling pathway. Nat Cell Biol 4, 367–373 (2002). https://doi.org/10.1038/ncb786

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb786

This article is cited by

Search

Advanced 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