Letter | Published:

LDL-receptor-related proteins in Wnt signal transduction

Nature volume 407, pages 530535 (28 September 2000) | Download Citation

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Abstract

The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation1. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors2,3,4,5,6,7,8,9,10, but how Fz proteins transduce signalling is not understood. In Drosophila , arrow phenocopies the wingless (DWnt-1) phenotype11, and encodes a transmembrane protein11 that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12,13,14, 15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt–Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt–Fz, but not by Dishevelled or β-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex.

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References

  1. 1.

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

  2. 2.

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

  3. 3.

    , , , & A frizzled homolog functions in a vertebrate Wnt signalling pathway. Curr. Biol. 6, 1302–1306 (1996).

  4. 4.

    et al. A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 275, 1652– 1654 (1997).

  5. 5.

    frizzled and frizzled 2 play a partially redundant role in wingless signalling and have similar requirements to wingless in neurogenesis. Cell 95, 1027–1036 ( 1998).

  6. 6.

    & Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell 95, 1017– 1026 (1998).

  7. 7.

    , & Wingless signalling in the Drosophila embryo: zygotic requirements and the role of the frizzled genes. Development 126, 577–586 ( 1999).

  8. 8.

    , , & Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl Acad. Sci. USA 96, 3546–3551 ( 1999).

  9. 9.

    et al. Frizzled and Dfrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development. Development 126, 4175–4186 ( 1999).

  10. 10.

    & Wingless transduction by the Frizzled and Frizzled2 proteins of Drosophila. Development 126, 5441–5452 (1999).

  11. 11.

    et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527 –530 (2000).

  12. 12.

    et al. Isolation and characterization of LRP6, a novel member of the low density lipoprotein receptor gene family. Biochem. Biophys. Res. Commun. 248, 879–888 (1998).

  13. 13.

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

  14. 14.

    et al. A new low density lipoprotein receptor related protein, LRP 5, is expressed in hepatocytes and adrenal cortex, and recognizes apolipoprotein E. J. Biochem. (Tokyo) 124, 1072– 1076 (1998).

  15. 15.

    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).

  16. 16.

    , , , & An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535– 538 (2000).

  17. 17.

    & Formation and function of Spemann's organizer. Annu. Rev. Cell Dev. Biol. 13, 611–667 (1997).

  18. 18.

    , , , & Wnt signalling required for expansion of neural crest and CNS progenitors. Nature 389, 966–970 (1997).

  19. 19.

    , , & Regulation of dorsal fate in the neuraxis by Wnt-1 and Wnt-3a. Proc. Natl Acad. Sci. USA 94, 13713–13718 (1997).

  20. 20.

    & Neural crest induction by Xwnt7B in Xenopus. Dev. Biol. 194, 129–134 (1998).

  21. 21.

    & Neural crest induction in Xenopus: evidence for a two signal model. Development 125, 2403–2414 (1998).

  22. 22.

    , & Control of neural crest cell fate by the Wnt signalling pathway. Nature 396, 370– 373 (1998).

  23. 23.

    , , & The putative Wnt receptor Xenopus frizzled-7 functions upstream of β-catenin in vertebrate dorsoventral mesoderm patterning. Development 127, 1981–1990 (2000).

  24. 24.

    et al. The mouse fused locus encodes Axin, an inhibitor of the Wnt signalling pathway that regulates embryonic axis formation. Cell 90, 181–192 (1997).

  25. 25.

    et al. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell 86, 391–399 (1996).

  26. 26.

    et al. Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc. Natl Acad. Sci. USA 94, 6770–6775 (1997).

  27. 27.

    & Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404 , 725–728 (2000).

  28. 28.

    et al. Reeler/Disabled-like disruption of neuronal migration in knockout mice lacking the VLDL receptor and ApoE receptor 2. Cell 97, 689–701 (1999).

  29. 29.

    , & Neuralization of the Xenopus embryo by inhibition of p300/CBP function. J. Neuroscience 19, 9346– 9373 (1999).

  30. 30.

    et al. Transformation by Wnt family proteins correlates with regulation of β-catenin. Cell Growth Differ. 8, 1349–1358 (1997).

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Acknowledgements

We thank M. Semenova for technical assistance; J. Heitz, J. Kitajewski, J. Nathans, S. Sokol, D. Sussman and A. Parlow (NHPP) for reagents; S. DiNardo and B. Skarnes for communication; and R. Habas, Z. He and Q. Ma for comments. X.H. acknowledges supports from Johnson and Johnson, the US Army, Susan G. Komen Foundation and the NIH. J.-P.S.-J. acknowledges supports from Johnson and Johnson and Whitehall Foundation. X.H. is a Pew Scholar and Klingenstein Fellow.

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  1. *Division of Neuroscience, Children's Hospital, Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA

    • Keiko Tamai
    • , Mikhail Semenov
    • , Yoichi Kato
    • , Chunming Liu
    • , Yu Katsuyama
    •  & Xi He
  2. †Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, Pennsylvania 19104 , USA

    • Rebecca Spokony
    •  & Jean-Pierre Saint-Jeannet
  3. ‡Department of Human Genetics, Merck Research Laboratories, PO Box 4, West Point, Pennsylvania 19486, USA

    • Fred Hess

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Correspondence to Xi He.

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https://doi.org/10.1038/35035117

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