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LDL-receptor-related proteins in Wnt signal transduction

Nature volume 407, pages 530–535 (2000)Cite this article

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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Figure 1: LRP6/LRP5 in Wnt signalling.
Figure 2: LRP6 in neural crest formation.
Figure 3: LRP6 functions in Wnt-responding cells.
Figure 4: LRP6 functions upstream of Dsh protein and is antagonized by FRP.
Figure 5: LRP6 extracellular domain binds Wnt-1 and complexes with mFz8CRD in the presence of Wnt-1.

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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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Authors and Affiliations

  1. Division of Neuroscience, Department of Neurology, Children's Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, 02115, Massachusetts, 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, 19104 , Pennsylvania, USA

    Rebecca Spokony & Jean-Pierre Saint-Jeannet

  3. Department of Human Genetics, Merck Research Laboratories, PO Box 4, West Point, 19486, Pennsylvania, USA

    Fred Hess

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Correspondence to Xi He.

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Tamai, K., Semenov, M., Kato, Y. et al. LDL-receptor-related proteins in Wnt signal transduction. Nature 407, 530–535 (2000). https://doi.org/10.1038/35035117

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