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Active Wnt proteins are secreted on exosomes

Abstract

Wnt signalling has important roles during development and in many diseases. As morphogens, hydrophobic Wnt proteins exert their function over a distance to induce patterning and cell differentiation decisions. Recent studies have identified several factors that are required for the secretion of Wnt proteins; however, how Wnts travel in the extracellular space remains a largely unresolved question. Here we show that Wnts are secreted on exosomes both during Drosophila development and in human cells. We demonstrate that exosomes carry Wnts on their surface to induce Wnt signalling activity in target cells. Together with the cargo receptor Evi/WIs, Wnts are transported through endosomal compartments onto exosomes, a process that requires the R-SNARE Ykt6. Our study demonstrates an evolutionarily conserved functional role of extracellular vesicular transport of Wnt proteins.

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Figure 1: Wnt proteins are secreted on exosomes.
Figure 2: Exosome-bound Wnt is active to induce signalling.
Figure 3: The secretory factor Evi is found on exosomes/shuttles Wnts on exosomes.
Figure 4: Mechanisms of MVB sorting of Wnt proteins.
Figure 5: Wingless is secreted on exosomes during Drosophila imaginal disc development.
Figure 6: Ykt6 is a required regulator for exosomal secretion of Wingless.
Figure 7: YKT6 blocks Wnt3A and exosome secretion.

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Acknowledgements

We thank T. Soellner, T. Buechling and D. Kranz for helpful comments on the manuscript. We would like to thank T. Vaccari, S. Eaton, S. Cohen, C. Niehrs, H. Bellen and the Bloomington stock centre for fly strains and reagents. We thank VDRC for the RNAi lines. We are grateful for help from the CellNetworks Electron Microscopy Core Facility (EMCF), the Light Microscopy Core Facility at the DKFZ and the Mass Spectrometry Core Facility at the DKFZ. J.C.G was supported by the CellNetworks postdoctoral fellowship programme. The DFG Wnt Research Group FOR1036 supported research in the laboratory of M.B.

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J.C.G. designed experiments, carried out the biochemical and cell-biological experiments and wrote the manuscript. V.C. designed experiments, carried out the in vivo experiments and wrote the manuscript. K.B. provided essential advice, generated in vivo reagents and contributed to writing the manuscript. M.B. designed experiments and wrote the manuscript.

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Correspondence to Michael Boutros.

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Gross, J., Chaudhary, V., Bartscherer, K. et al. Active Wnt proteins are secreted on exosomes. Nat Cell Biol 14, 1036–1045 (2012). https://doi.org/10.1038/ncb2574

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