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

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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, Peters, Peter J., Maurice, Madelon M., Clevers, Hans·2016·Nature

DOI 10.1038/nature16937

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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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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: Farin, Henner F.
Jordens, Ingrid
Mosa, Mohammed H.
Tauriello, Daniele V. F.
Peters, Peter J.
Maurice, Madelon M.
Clevers, Hans
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2016-02
Volume: 530
Issue: 7590
Pages: 340-343
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature16937
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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Visualization of a short-range Wnt gradient in the intestinal stem-cell niche

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