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A new secreted protein that binds to Wnt proteins and inhibits their activites

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Abstract

The Wnt proteins constitute a large family of extracellular signalling molecules that are found throughout the animal kingdom and are important for a wide variety of normal and pathological developmental processes1,2. Here we describe Wnt-inhibitory factor-1 (WIF-1), a secreted protein that binds to Wnt proteins and inhibits their activities. WIF-1 is present in fish, amphibia and mammals, and is expressed during Xenopus and zebrafish development in a complex pattern that includes paraxial presomitic mesoderm, notochord, branchial arches and neural crest derivatives. We use Xenopus embryos to show that WIF-1 overexpression affects somitogenesis (the generation of trunk mesoderm segments), in agreement with its normal expression in paraxial mesoderm. In vitro, WIF-1 binds to Drosophila Wingless and Xenopus Wnt8 produced by Drosophila S2 cells. Together with earlier results obtained with the secreted Frizzled-related proteins1,2, our results indicate that Wnt proteins interact with structurally diverse extracellular inhibitors, presumably to fine-tune the spatial and temporal patterns of Wnt activity.

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Figure 1: Sequence alignment and structure of vertebrate WIF-1.
Figure 2: Expression of WIF-1 in the adult mouse and during Xenopus and zebrafish development.
Figure 3: WIF-1 inhibits Wnt signaling and affects somite formation in Xenopus embryos.
Figure 4: hWIF-1 binds reversibly to soluble Wg and XWnt8–Myc and inhibits the Wg response of clone-8 cells.

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Acknowledgements

We thank R. Moon for Xwnt8-Myc cDNA, J. Flanagan for the alkaline phosphatase plasmid, J. Corden for the mouse RNA polymerase II clone, B. Appel, L. Roman and D. Grunwald for cDNA libraries, and P. Bhanot and I. Munoz-Sanjuan for comments on the manuscript. Supported by the Howard Hughes Medical Institute (J.-C.H., A.R., P.M.S., C.H.S., R.N., J.N.).

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  1. Jen-Chih Hsieh and Laurent Kodjabachian: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jen-Chih Hsieh, Amir Rattner, Philip M. Smallwood & Jeremy Nathans

  2. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jen-Chih Hsieh, Amir Rattner, Philip M. Smallwood & Jeremy Nathans

  3. Departments of Neuroscience and Ophthalmology, Johns Hopkins University School of Medicine, Baltimore, 21205, Maryland, USA

    Jeremy Nathans

  4. Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892, Maryland, USA

    Laurent Kodjabachian, Martha L. Rebbert & Igor B. Dawid

  5. Department of Developmental Biology, Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, 94035, California, USA

    Cynthia Harryman Samos & Roel Nusse

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  1. Jen-Chih Hsieh
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  2. Laurent Kodjabachian
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Correspondence to Jeremy Nathans.

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Hsieh, JC., Kodjabachian, L., Rebbert, M. et al. A new secreted protein that binds to Wnt proteins and inhibits their activites. Nature 398, 431–436 (1999). https://doi.org/10.1038/18899

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  • DOI: https://doi.org/10.1038/18899

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