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An LDL-receptor-related protein mediates Wnt signalling in mice

Nature volume 407, pages 535–538 (2000)Cite this article

Abstract

Wnt genes comprise a large family of secreted polypeptides that are expressed in spatially and tissue-restricted patterns during vertebrate embryonic development1. Mutational analysis in mice has shown the importance of Wnts in controlling diverse developmental processes such as patterning of the body axis, central nervous system and limbs, and the regulation of inductive events during organogenesis2. Although many components of the Wnt signalling pathway have been identified, little is known about how Wnts and their cognate Frizzled receptors signal to downstream effector molecules. Here we present evidence that a new member of the low-density lipoprotein (LDL)-receptor-related protein family, LRP6 (ref. 3), is critical for Wnt signalling in mice. Embryos homozygous for an insertion mutation in the LRP6 gene exhibit developmental defects that are a striking composite of those caused by mutations in individual Wnt genes. Furthermore, we show a genetic enhancement of a Wnt mutant phenotype in mice lacking one functional copy of LRP6. Together, our results support a broad role for LRP6 in the transduction of several Wnt signals in mammals.

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Figure 1: LRP6 mutant embryos exhibit severe developmental defects
Figure 2: Abnormal tailbud and caudal somite formation in LRP6-deficient embryos.
Figure 3: The LRP6 mutation enhances the vestigial tail phenotype.
Figure 4: Caudal midbrain and cerebellar defects in LRP6 mutant embryos.
Figure 5: LRP6 mutant limbs show patterning and AER defects.

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References

  1. Wodarz, A. & Nusse, R. Mechanisms of Wnt signalling in development. Annu. Rev. Cell Dev. Biol. 14, 59– 89 (1998).

    Article  CAS  Google Scholar 

  2. Uusitalo, M., Heikkila, M. & Vainio, S. Molecular genetic studies of Wnt signalling in the mouse. Exp. Cell Res. 253, 336– 348 (1999).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  4. Skarnes, W. C., Moss, J. E., Hurtley, S. M. & Beddington, R. S. P. Capturing genes encoding membrane and secreted proteins important for mouse development. Proc. Natl Acad. Sci. USA 92, 6592–6596 (1995).

    Article  ADS  CAS  Google Scholar 

  5. Takada, S. et al.Wnt-3a regulates somite and tailbud formation in the mouse embryo. Genes Dev. 8, 174–189 (1994).

    Article  CAS  Google Scholar 

  6. Yoshikawa, Y., Fujimori, T., McMahon, A. P. & Takada, S. Evidence that absence of Wnt-3a signalling promotes neuralization instead of paraxial mesoderm development in the mouse. Dev. Biol. 183, 234–242 (1997).

    Article  CAS  Google Scholar 

  7. Greco, T. L. et al. Analysis of the vestigial tail mutation demonstrates that Wnt-3a gene dosage regulates mouse axial development. Genes Dev. 10, 313–324 ( 1996).

    Article  CAS  Google Scholar 

  8. McMahon, A. P. & Bradley, A. The Wnt-1 (int-1) proto-oncogene is required for development of a large region of the mouse brain. Cell 62, 1073–1085 ( 1990).

    Article  CAS  Google Scholar 

  9. Thomas, K. R. & Capecchi, M. R. Targeted disruption of the murine int-1 proto-oncogene resulting in severe abnormalities in midbrain and cerebellar development. Nature 346, 847– 850 (1990).

    Article  ADS  CAS  Google Scholar 

  10. Thomas, K. R., Musci, T. S., Neumann, P. E. & Capecchi, M. R. Swaying is a mutant allele of the proto-oncogene Wnt-1. Cell 67, 969–976 ( 1991).

    Article  CAS  Google Scholar 

  11. Bally-Cuif, L., Cholley, B. & Wassef, M. Involvement of Wnt-1 in the formation of the mes/metencephalic boundary. Mech. Dev. 53, 23– 34 (1995).

    Article  CAS  Google Scholar 

  12. Parr, B. A. & McMahon, A. P. Dorsalizing signal Wnt-7a required for normal polarity of D–V and A–P axes of mouse limb. Nature 374, 350–353 ( 1995).

    Article  ADS  CAS  Google Scholar 

  13. Yang, Y. & Niswander, L. Interaction between the signalling molecules WNT7a and SHH during vertebrate limb development: dorsal signals regulate anteroposterior patterning. Cell 80, 939–947.

  14. Liu, P. et al. Requirement for Wnt3 in vertebrate axis formation. Nature Genet. 22, 361–365 ( 1999).

    Article  CAS  Google Scholar 

  15. Yamaguchi, T. P., Bradley, A., McMahon, A. P. & Jones, S. A. Wnt5a pathway underlies outgrowth of mutiple structures in the vertebrate embryo. Development 126, 1211– 1223 (1999).

    CAS  PubMed  Google Scholar 

  16. 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 

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

    Article  ADS  Google Scholar 

  18. Tamai, K. et al. LDL receptor-related proteins in Wnt signal transduction. Nature (this issue).

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

    Article  ADS  CAS  Google Scholar 

  20. Willnow, T. E. The low-density lipoprotein receptor gene family: multiple roles in lipid metabolism. J. Mol. Med. 77, 306– 315 (1999).

    Article  CAS  Google Scholar 

  21. 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  Google Scholar 

  22. Townley, D. J., Avery, B. J., Rosen, B. & Skarnes, W. C. Rapid sequence analysis of gene trap integrations to generate a resource of insertional mutations in mice. Genome Res. 7, 293– 298 (1997).

    Article  CAS  Google Scholar 

  23. Brennan, J. & Skarnes, W. C. in Methods in Molecular Biology, Molecular Embryology: Methods and Protocols Vol. 97 (eds Sharpe, P. & Mason, I.) 123–138 (Humana Press, Totowa, NJ, 1999).

    Book  Google Scholar 

  24. Hogan, B., Beddington, R., Constantini, F. & Lacy, E. (eds) Manipulating the Mouse Embryo: A Laboratory Manual 2nd edn 260 –261 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, 1994).

    Google Scholar 

  25. Wilkinson, D. G. & Nieto, M. A. Detection of messenger RNA by in situ hybridization to tissue sections and whole mounts. Methods Enzymol. 225, 361– 367 (1993).

    Article  CAS  Google Scholar 

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Acknowledgements

We wish to thank F. Hess for providing us with the mouse LRP5 and LRP6 cDNAs; V. Wilson, J. Rubenstein and T. Greco for helpful discussions; A. Peterson, J. Rine, G. Garriga and members of the lab for critical comments on the manuscript. This work was funded in part by the Biotechnology and Biological Sciences Research Council (UK), the Chicago Community Trust and a grant from the March of Dimes. W.C.S. is a 1998 Searle Scholar.

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Author notes

  1. Jane Brennan

    Present address: Department of Molecular & Cell Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts, 02138, USA

  2. Susan Monkley

    Present address: Department of Biochemistry, University of Leicester, Leicester, LE1 7RH, UK

  3. Correspondence and requests for materials should be addressed to W.C.S..

Authors and Affiliations

  1. Department of Molecular and Cell Biology, University of California, Berkeley, 94720, California, USA

    Jane Brennan, Susan Monkley, Brian J. Avery & William C. Skarnes

  2. Department of Molecular & Cell Biology, Harvard University, 16 Divinity Avenue, Cambridge, Massachusetts, 02138, USA

    Kathleen I. Pinson

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Pinson, K., Brennan, J., Monkley, S. et al. An LDL-receptor-related protein mediates Wnt signalling in mice. Nature 407, 535–538 (2000). https://doi.org/10.1038/35035124

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