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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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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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