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Wingless secretion requires endosome-to-Golgi retrieval of Wntless/Evi/Sprinter by the retromer complex

Nature Cell Biology volume 10, pages 170177 (2008) | Download Citation

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Abstract

The glycolipoproteins of the Wnt family raise interesting trafficking issues, especially with respect to spreading within tissues. Recently, the retromer complex has been suggested to participate in packaging Wnts into long-range transport vehicles1,2. Our analysis of a Drosophila mutant in Vps35 show that, instead, the retromer complex is required for efficient progression of Wingless (a Drosophila Wnt) through the secretory pathway. Indeed expression of senseless, a short-range target gene3, is lost in Vps35-deficient imaginal discs. In contrast, Vps35 is not required for Hedgehog secretion, suggesting specificity. Overexpression of Wntless, a transmembrane protein known to be specifically required for Wingless secretion4,5,6 overcomes the secretion block of Vps35-mutant cells. Furthermore, biochemical evidence confirms that Wntless engages with the retromer complex. We propose that Wntless accompanies Wingless to the plasma membrane where the two proteins dissociate. Following dissociation from Wingless, Wntless is internalized and returns to the Golgi apparatus in a retromer-dependent manner. Without the retromer-dependent recycling route, Wingless secretion is impaired and, as electron microscopy suggests, Wntless is diverted to a degradative compartment.

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Acknowledgements

We thank M. Seaman, S. Eaton, H. Bellen, I. Duncan, I. Guerrero and the Developmental Studies Hybridoma Bank (Iowa University) for antibodies. We also thank the Bloomington Stock Center (Indiana University) for numerous Drosophila strains. This work was largely funded by the Medical Research Council of Great Britain. Additional funding was provided by the Endotrack program of the European Union (J.P.V.) and the Dutch Cancer Society grant UU2006-3508 (M.M.). A.B.-L. is funded by an EMBO fellowship (740-2006). C. Alexandre, M. Hannah and I. Salecker provided critical comments on the manuscript.

Author information

Author notes

    • Xavier Franch-Marro
    •  & Franz Wendler

    These authors contributed equally to this work.

Affiliations

  1. MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.

    • Xavier Franch-Marro
    • , Franz Wendler
    • , Sonia Guidato
    • , Alberto Baena-Lopez
    • , Nobue Itasaki
    •  & Jean-Paul Vincent
  2. Department of Cell Biology, University Medical Center Utrecht (UMCU), Heidelberglaan 100, 3584CX Utrecht, The Netherlands.

    • Janice Griffith
    •  & Madelon M. Maurice

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Contributions

F.W., X.F. and J.P.V. conceived the project; X. F. performed most of the Drosophila work with substantial support from F.W. and some help from A.B.L.; S.G., F.W. and N.I. performed and analysed most of the cell culture experiments. J.G. and M.M. performed and analysed the electron microscopy; F.W. and J.P.V. wrote the first draft of the manuscript with subsequent contributions from all authors.

Corresponding author

Correspondence to Jean-Paul Vincent.

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DOI

https://doi.org/10.1038/ncb1678

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