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Nature. 2016 Feb 18;530(7590):340-3. doi: 10.1038/nature16937. Epub 2016 Feb 10.

Visualization of a short-range Wnt gradient in the intestinal stem-cell niche.

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Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands.
German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany.
German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands.
The Maastricht Multimodal Molecular Imaging institute, Maastricht University, 6229ER Maastricht, the Netherlands.
Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.


Mammalian Wnt proteins are believed to act as short-range signals, yet have not been previously visualized in vivo. Self-renewal, proliferation and differentiation are coordinated along a putative Wnt gradient in the intestinal crypt. Wnt3 is produced specifically by Paneth cells. Here we have generated an epitope-tagged, functional Wnt3 knock-in allele. Wnt3 covers basolateral membranes of neighbouring stem cells. In intestinal organoids, Wnt3-transfer involves direct contact between Paneth cells and stem cells. Plasma membrane localization requires surface expression of Frizzled receptors, which in turn is regulated by the transmembrane E3 ligases Rnf43/Znrf3 and their antagonists Lgr4-5/R-spondin. By manipulating Wnt3 secretion and by arresting stem-cell proliferation, we demonstrate that Wnt3 mainly travels away from its source in a cell-bound manner through cell division, and not through diffusion. We conclude that stem-cell membranes constitute a reservoir for Wnt proteins, while Frizzled receptor turnover and 'plasma membrane dilution' through cell division shape the epithelial Wnt3 gradient.

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