LDL-receptor-related proteins in Wnt signal transduction (original) (raw)
- Letter
- Published: 28 September 2000
- Mikhail Semenov1,
- Yoichi Kato1,
- Rebecca Spokony2,
- Chunming Liu1,
- Yu Katsuyama1,
- Fred Hess3,
- Jean-Pierre Saint-Jeannet2 &
- …
- Xi He1
Nature volume 407, pages 530–535 (2000)Cite this article
- 5532 Accesses
- 19 Altmetric
- Metrics details
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Additional access options:
Similar content being viewed by others
References
- Wodarz, A. & Nusse, R. Mechanisms of Wnt signalling in development. Annu. Rev. Cell Dev. Biol. 14, 59– 88 (1998).
Article CAS PubMed Google Scholar - 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 PubMed Google Scholar - Yang-Snyder, J., Miller, J. R., Brown, J. D., Lai, C. J. & Moon, R. T. A frizzled homolog functions in a vertebrate Wnt signalling pathway. Curr. Biol. 6, 1302–1306 (1996).
Article CAS PubMed Google Scholar - He, X. et al. A member of the Frizzled protein family mediating axis induction by Wnt-5A. Science 275, 1652– 1654 (1997).
Article CAS PubMed Google Scholar - Bhat, K. M. 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).
Article CAS PubMed Google Scholar - Kennerdell, J. R. & Carthew, R. W. Use of dsRNA-mediated genetic interference to demonstrate that frizzled and frizzled 2 act in the wingless pathway. Cell 95, 1017– 1026 (1998).
Article CAS PubMed Google Scholar - Muller, 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).
CAS PubMed Google Scholar - Hsieh, J. C., Rattner, A., Smallwood, P. M. & Nathans, J. Biochemical characterization of Wnt-frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl Acad. Sci. USA 96, 3546–3551 ( 1999).
Article ADS CAS PubMed PubMed Central Google Scholar - Bhanot, P. et al. Frizzled and Dfrizzled-2 function as redundant receptors for Wingless during Drosophila embryonic development. Development 126, 4175–4186 ( 1999).
CAS PubMed Google Scholar - Chen, C. M. & Struhl, G. Wingless transduction by the Frizzled and Frizzled2 proteins of Drosophila. Development 126, 5441–5452 (1999).
CAS PubMed Google Scholar - Wehrli, M. et al. arrow encodes an LDL-receptor-related protein essential for Wingless signalling. Nature 407, 527 –530 (2000).
Article ADS CAS PubMed Google Scholar - Brown, S. D. 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).
Article CAS PubMed Google Scholar - Hey, P. J. et al. Cloning of a novel member of the low-density lipoprotein receptor family. Gene 216, 103–111 (1998).
Article CAS PubMed Google Scholar - Kim, D. H. 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).
Article CAS Google Scholar - 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 PubMed Google Scholar - Pinson, K. I., Brennan, J., Monkley, S., Avery, B & Skarnes, W. C. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535– 538 (2000).
Article ADS CAS PubMed Google Scholar - Harland, R. M. & Gerhart, J. Formation and function of Spemann's organizer. Annu. Rev. Cell Dev. Biol. 13, 611–667 (1997).
Article CAS PubMed Google Scholar - Ikeya, M., Lee, S. M. K., Johnson, J. E., McMahon, A. P. & Takada, S. Wnt signalling required for expansion of neural crest and CNS progenitors. Nature 389, 966–970 (1997).
Article ADS CAS PubMed Google Scholar - Saint-Jeannet, J.-P., He, X., Varmus, H. E. & Dawid, I. B. Regulation of dorsal fate in the neuraxis by Wnt-1 and Wnt-3a. Proc. Natl Acad. Sci. USA 94, 13713–13718 (1997).
Article ADS CAS PubMed PubMed Central Google Scholar - Chang, C. & Hemmati-Brivanlou, A. Neural crest induction by Xwnt7B in Xenopus. Dev. Biol. 194, 129–134 (1998).
Article CAS PubMed Google Scholar - LaBonne, C. & Bronner-Fraser, M. Neural crest induction in Xenopus: evidence for a two signal model. Development 125, 2403–2414 (1998).
CAS PubMed Google Scholar - Dorsky, R. I., Moon, R. T. & Raible, D. W. Control of neural crest cell fate by the Wnt signalling pathway. Nature 396, 370– 373 (1998).
Article ADS CAS PubMed Google Scholar - Sumanas, S., Strege, P., Heasman, J., & Ekker, S. C. The putative Wnt receptor Xenopus frizzled-7 functions upstream of β-catenin in vertebrate dorsoventral mesoderm patterning. Development 127, 1981–1990 (2000).
CAS PubMed Google Scholar - Zeng, L. 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).
Article CAS PubMed Google Scholar - Molenaar, M. et al. XTcf-3 transcription factor mediates β-catenin-induced axis formation in Xenopus embryos. Cell 86, 391–399 (1996).
Article CAS PubMed Google Scholar - Finch, P. W. et al. Purification and molecular cloning of a secreted, Frizzled-related antagonist of Wnt action. Proc. Natl Acad. Sci. USA 94, 6770–6775 (1997).
Article ADS CAS PubMed PubMed Central Google Scholar - Perrimon, N. & Bernfield, M. Specificities of heparan sulphate proteoglycans in developmental processes. Nature 404 , 725–728 (2000).
Article ADS CAS PubMed Google Scholar - Trommsdorff, M. 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).
Article CAS PubMed Google Scholar - Kato, Y., Shi, Y. & He, X. Neuralization of the Xenopus embryo by inhibition of p300/CBP function. J. Neuroscience 19, 9346– 9373 (1999).
Article Google Scholar - Shimizu, H. et al. Transformation by Wnt family proteins correlates with regulation of β-catenin. Cell Growth Differ. 8, 1349–1358 (1997).
MathSciNet CAS PubMed Google Scholar
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.
Author information
Authors and Affiliations
- 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 - Department of Animal Biology, School of Veterinary Medicine, University of Pennsylvania, 3800 Spruce Street, Philadelphia, 19104 , Pennsylvania, USA
Rebecca Spokony & Jean-Pierre Saint-Jeannet - Department of Human Genetics, Merck Research Laboratories, PO Box 4, West Point, 19486, Pennsylvania, USA
Fred Hess
Authors
- Keiko Tamai
You can also search for this author inPubMed Google Scholar - Mikhail Semenov
You can also search for this author inPubMed Google Scholar - Yoichi Kato
You can also search for this author inPubMed Google Scholar - Rebecca Spokony
You can also search for this author inPubMed Google Scholar - Chunming Liu
You can also search for this author inPubMed Google Scholar - Yu Katsuyama
You can also search for this author inPubMed Google Scholar - Fred Hess
You can also search for this author inPubMed Google Scholar - Jean-Pierre Saint-Jeannet
You can also search for this author inPubMed Google Scholar - Xi He
You can also search for this author inPubMed Google Scholar
Corresponding author
Correspondence toXi He.
Rights and permissions
About this article
Cite this article
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
- Received: 14 June 2000
- Accepted: 28 July 2000
- Issue Date: 28 September 2000
- DOI: https://doi.org/10.1038/35035117