The DOI matches its Crossref record; 38 of the 38 references it cites were found in a registry or an index.
Visualization of a short-range Wnt gradient in the intestinal stem-cell niche
Abstract
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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In the citing paper
“Because it was recently reported that Wnt3 transfer requires direct cell contact and has only a very limited range (Farin et al., 2016), the most likely cellular source of Wnts that influence Wnt signaling upon aging might thus be mostly Paneth cells and, in part, mesenchyme.”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Farin et al., 2016
In the citing paper
“Because it was recently reported that Wnt3 transfer requires direct cell contact and has only a very limited range (Farin et al., 2016)”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Farin et al., 2016
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Cites
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204
Self-citationIdentification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687
Self-citationPaneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Sato, T., van Es, J. H., Snippert, H. J., Stange, D. E., Vries, R. G., van den Born, M., Barker, N., Shroyer, N. F., van de Wetering, M., & Clevers, H. (2011) · Nature · doi:10.1038/nature09637 · Cited by 2,510
Self-citationSchwank, G., Koo, B.-K., Sasselli, V., Dekkers, J. F., Heo, I., Demircan, T., Sasaki, N., Boymans, S., Cuppen, E., van der Ent, C. K., et al. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.11.002 · Cited by 1,424
Self-citationSmall molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
Chen, B., Dodge, M. E., Tang, W., Lü, J., Ma, Z., Fan, C.-W., Wei, S., Hao, W., Kilgore, J. A., Williams, N. S., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.137 · Cited by 1,402
The intestinal crypt, a prototype stem cell compartment
Clevers, H. (2013) · Cell · doi:10.1016/j.cell.2013.07.004 · Cited by 1,223
Self-citationTissue‐specific and inducible Cre‐mediated recombination in the gut epithelium
Marjou, F. E., Janssen, K., Chang, B. H., Li, M., Hindie, V., Chan, L., Louvard, D., Chambon, P., METZGER, D., & Robine, S. (2004) · genesis · doi:10.1002/gene.20042 · Cited by 1,087
Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, B.-K., Spit, M., Jordens, I., Low, T. Y., Stange, D. E., van de Wetering, M., van Es, J. H., Mohammed, S., Heck, A. J. R., Maurice, M. M., et al. (2012) · Nature · doi:10.1038/nature11308 · Cited by 980
Self-citationZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
Hao, H.-X., Xie, Y., Zhang, Y., Charlat, O., Oster, E., Avello, M., Lei, H., Mickanin, C., Liu, D., Ruffner, H., et al. (2012) · Nature · doi:10.1038/nature11019 · Cited by 962
Structural Basis of Wnt Recognition by Frizzled
Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & García, K. C. (2012) · Science · doi:10.1126/science.1222879 · Cited by 901
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Wnt/β-Catenin Signaling, Disease, and Emerging Therapeutic Modalities
Nusse, R., & Clevers, H. (2017) · Cell · doi:10.1016/j.cell.2017.05.016 · Cited by 4,342
Self-citationZhan, T., Rindtorff, N., & Boutros, M. (2017) · Oncogene · doi:10.1038/onc.2016.304 · Cited by 2,626
Progress and potential in organoid research
Rossi, G., Manfrin, A., & Lutolf, M. P. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0051-9 · Cited by 1,182
Tales from the crypt: new insights into intestinal stem cells
Gehart, H., & Clevers, H. C. (2018) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-018-0081-y · Cited by 1,046
Self-citationWnt signaling in development and tissue homeostasis
Steinhart, Z., & Angers, S. (2018) · Development · doi:10.1242/dev.146589 · Cited by 821
Self-citation
Metadata
- Authors
- Farin, H. F., Jordens, I., Mosa, M. H., Basak, O., Korving, J., Tauriello, D. V. F., de Punder, K., Angers, S., Peters, P. J., Maurice, M. M., & Clevers, H.
- Affiliations
- Royal Netherlands Academy of Arts and Sciences (NL)
- University Medical Center Utrecht (NL)
- German Cancer Research Center (DE)
- Maastricht University (NL)
- Corresponding author
- Farin, Henner F.
- Clevers, Hans
- ORCID
- Venue
- Nature
- Published
- 2016-02
- Volume
- 530
- Issue
- 7590
- Pages
- 340-343
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2258083311
- Cited by
- 525
- References
- 38
- Citations by year
- 2026: 27 · 2025: 41 · 2024: 31 · 2023: 48 · 2022: 47 · 2021: 46 · 2020: 55 · 2019: 56 · 2018: 76 · 2017: 62 · 2016: 35
- FWCI
- 39.70
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Keywords
- Wnt3, Wnt signaling, intestinal stem cells, Paneth cells, short-range signaling, intestinal crypts, intestinal organoids, Frizzled receptors, cell division, stem cell self-renewal
- MeSH terms
- Alleles, Animals, Cell Adhesion, Cell Division, Cell Membrane, Diffusion, Female, Intestinal Mucosa, Male, Organoids, Stem Cells, Paneth Cells, Intercellular Signaling Peptides and Proteins, Receptors, G-Protein-Coupled, Ubiquitin-Protein Ligases, Frizzled Receptors, Mice, Stem Cell Niche, Gene Knock-In Techniques, Wnt Signaling Pathway, Wnt3 Protein
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