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.

  • Letter
  • Published:

arrow encodes an LDL-receptor-related protein essential for Wingless signalling

A Corrigendum to this article was published on 12 April 2001

Abstract

The Wnt family of secreted molecules functions in cell-fate determination and morphogenesis during development in both vertebrates and invertebrates (reviewed in ref. 1). Drosophila Wingless is a founding member of this family, and many components of its signal transduction cascade have been identified, including the Frizzled class of receptor. But the mechanism by which the Wingless signal is received and transduced across the membrane is not completely understood. Here we describe a gene that is necessary for all Wingless signalling events in Drosophila. We show that arrow gene function is essential in cells receiving Wingless input and that it acts upstream of Dishevelled. arrow encodes a single-pass transmembrane protein, indicating that it may be part of a receptor complex with Frizzled class proteins. Arrow is a low-density lipoprotein (LDL)-receptor-related protein (LRP), strikingly homologous to murine and human LRP5 and LRP6. Thus, our data suggests a new and conserved function for this LRP subfamily in Wingless/Wnt signal reception.

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: Arrow is required for Wg-dependent cell fates.
Figure 2: arr functions downstream of wg but upstream of dsh .
Figure 3: Arrow is a member of the LDL-receptor protein family.
Figure 4: arrow is required cell-autonomously for Wg target gene expression.
Figure 5: Ectopic expression of Arrow mimics ligand-dependent pathway activation.

Similar content being viewed by others

References

  1. Wodarz, A. & Nusse, R. Mechanisms of Wnt signalling in development. Annu. Rev. Cell Dev. Biol. 14, 59– 88 (1998).

    Article  CAS  Google Scholar 

  2. Dougan, S. T. & DiNardo, S. wingless generates cell type diversity among engrailed expressing cells. Nature 360, 347–350 (1992).

    Article  ADS  CAS  Google Scholar 

  3. Bhanot, P. et al. A new member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382, 225–230 (1996).

    Article  ADS  CAS  Google Scholar 

  4. Müller, H., Samanta, R. & Wieschaus, E. Wingless signalling in the Drosophila embryo: zygotic requirements and the role of the frizzled genes. Development 126, 577–586 ( 1999).

    PubMed  Google Scholar 

  5. Klingensmith, J., Nusse, R. & Perrimon, N. The Drosophila segment polarity gene dishevelled encodes a novel protein required for response to the wingless signal. Genes Dev. 8, 118– 130 (1994).

    Article  CAS  Google Scholar 

  6. Riggleman, B., Schedl, P. & Wieschaus, E. Spatial expression of the Drosophila segment polarity gene armadillo is posttranscriptionally regulated by wingless . Cell 63, 549–560 (1990).

    Article  CAS  Google Scholar 

  7. Hey, P. J. et al. Cloning of a novel member of the low–density lipoprotein receptor family. Gene 216, 103– 111 (1998).

    Article  CAS  Google Scholar 

  8. Kim, D. H. et al. A new low density lipoprotein receptor related protein, LRP5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J. Biochem. (Tokyo) 124, 1072– 1076 (1998).

    Article  CAS  Google Scholar 

  9. Dong, Y. et al. Molecular cloning and characterization of LR3, a novel LDL receptor family protein with mitogenic activity. Biochem. Biophys. Res. Commun. 251, 784–790 ( 1998).

    Article  CAS  Google Scholar 

  10. Chen, D., Lathrop, W. & Dong, Y. Molecular cloning of mouse Lrp7(Lr3) cDNA and chromosomal mapping of orthologous genes in mouse and human. Genomics 55, 314–321 (1999).

    Article  CAS  Google Scholar 

  11. Brown, M. S., Herz, J. & Goldstein, J. L. LDL-receptor structure. Calcium cages, acid baths and recycling receptors. Nature 388, 629 –630 (1997).

    Article  ADS  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  13. 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 

  14. Brook, W. J. & Cohen, S. M. Antagonistic interactions between wingless and decapentaplegic responsible for dorsal–ventral pattern in the Drosophila leg. Science 273, 1373–1377 (1996).

    Article  ADS  CAS  Google Scholar 

  15. Jiang, J. & Struhl, G. Complementary and mutually exclusive activities of decapentaplegic and wingless organize axial patterning during Drosophila leg development. Cell 86, 401–409 (1996).

    Article  CAS  Google Scholar 

  16. Penton, A. & Hoffmann, F. M. Decapentaplegic restricts the domain of wingless during Drosophila limb patterning. Nature 382, 162–164 ( 1996).

    Article  ADS  CAS  Google Scholar 

  17. Heslip, T. R., Theisen, H., Walker, H. & Marsh, J. L. Shaggy and dishevelled exert opposite effects on Wingless and Decapentaplegic expression and on positional identity in imaginal discs. Development 124, 1069–1078 (1997).

    CAS  PubMed  Google Scholar 

  18. Perrimon, N. & Bernfield, M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404 , 725–728 (2000).

    Article  ADS  CAS  Google Scholar 

  19. Cadigan, K. M., Fish, M. P., Rulifson, E. J. & Nusse, R. Wingless repression of Drosophila frizzled 2 expression shapes the Wingless morphogen gradient in the wing. Cell 93, 767–777 (1998).

    Article  CAS  Google Scholar 

  20. Chen, C. & Struhl, G. Wingless transduction by the frizzled and frizzled2 proteins of Drosophila. Development 126, 5441–5452 (1999).

    CAS  PubMed  Google Scholar 

  21. Pinson, K., Brennan, J., Monkley, S., Avery, B. & Skarnes, W. C. An LDL-receptor-related protein, regulates Wnt signalling in mice. Nature 407, 535– 538 (2000).

    Article  ADS  CAS  Google Scholar 

  22. Wehrli, M. & Tomlinson, A. Independent regulation of anterior/posterior and equatorial/polar polarity in the Drosophila eye; evidence for the involvement of Wnt signalling in the equatorial/polar axis. Development 125, 1421–1432 ( 1998).

    CAS  PubMed  Google Scholar 

  23. Tamai, K. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530–535 ( 2000).

    Article  ADS  CAS  Google Scholar 

  24. Axelrod, J. D., Miller, J. R., Shulman, J. M., Moon, R. T. & Perrimon, N. Differential recruitment of Dishevelled provides signalling specificity in the planar cell polarity and Wingless signalling pathways. Genes Dev. 12, 2610– 2622 (1998).

    Article  CAS  Google Scholar 

  25. Rice, D. S. & Curran, T. Mutant mice with scrambled brains: understanding the signalling pathways that control cell positioning in the CNS. Genes Dev. 13, 2758– 5873 (1999).

    Article  CAS  Google Scholar 

  26. Senzaki, K., Ogawa, M. & Yagi, T. Proteins of the CNR family are multiple receptors for Reelin. Cell 99, 635–647 ( 1999).

    Article  CAS  Google Scholar 

  27. Brown, N. H. & Kafatos, F. C. Functional cDNA libraries from Drosophila embryos. J. Mol. Biol. 203, 425–437 (1988).

    Article  CAS  Google Scholar 

  28. Chou, T. B., Noll, E. & Perrimon, N. Autosomal P[ovoD1] dominant female-sterile insertions in Drosophila and their use in generating germ-line chimeras. Development 119, 1359–1369 (1993).

    CAS  PubMed  Google Scholar 

  29. Wehrli, M. & Tomlinson, A. Epithelial planar polarity in the developing Drosophila eye. Development 121 , 2451–2459 (1995).

    CAS  PubMed  Google Scholar 

  30. Nüsslein–Volhard, C., Wieschaus, E. & Kluding, H. Mutations affecting the pattern of the larval cuticle in Drosophila melanogaster I Zygotic loci on the second chromosome . Roux's Arch. Dev. Biol. 193 , 267–282 (1984).

    Article  Google Scholar 

Download references

Acknowledgements

G. Campbell, G. Struhl, F. Diaz-Benjumea, S. Cohen, R. Goto-Mandeville, E. Bieschke and B. Calvi provided insightful suggestions and help along the way. The free exchange of information with the Skarnes lab is acknowledged. The manuscript was improved by comments from N. Erdeniz, P. Klein, B. Wilder and the DiNardo lab. Material provided by J. Szidonya, the Bloomington Stock Center and Berkeley Drosophila Genome Project was of great importance. Supported by the Swiss National Science Foundation (M.W.), NIH (A.T. and S.D.) and American Cancer Society (S.D.).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Stephen DiNardo.

Supplementary information

Supplementary Information

Supplementary Information (PDF 200 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wehrli, M., Dougan, S., Caldwell, K. et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527–530 (2000). https://doi.org/10.1038/35035110

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/35035110

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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