Cited by 525Wnt/β-catenin signaling in development and cancerDevelopmental Biology and Gene RegulationHedgehog Signaling Pathway Studies

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

Farin, Henner F., Jordens, Ingrid, Mosa, Mohammed H., Basak, Onur, Korving, Jeroen, Tauriello, Daniele V. F., de Punder, Karin, Angers, Stephane +3 more·2016·Nature

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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Crossref · 10.1038/nature16937

Cites

38 of 38 references verified0 citation errors · 0 not checkable

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  • The most likely cellular source of Wnts influencing Wnt signaling upon aging is mostly Paneth cells and in part mesenchyme.

    “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

  • Wnt3 transfer requires direct cell contact and has only a very limited range.

    “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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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
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 · 2014: 1
FWCI
39.70
Type
journal article
Language
en
Open access
closed
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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