Cited by 656Wnt/β-catenin signaling in development and cancerDigestive system and related healthCancer Cells and Metastasis

Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells

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Farin, Henner F., Van Es, Johan H., Clevers, Hans·2012·Gastroenterology

Abstract

Background & aims Wnt signaling regulates multiple aspects of intestinal physiology, including stem cell maintenance. Paneth cells support stem cells by secreting Wnt, but little is known about the exact sources and primary functions of individual Wnt family members.Methods We analyzed intestinal tissues and cultured epithelial cells from adult mice with conditional deletion of Wnt3 (Vil-CreERT2;Wnt3fl/fl mice). We also analyzed intestinal tissues and cells from Atoh1 mutant mice, which lack secretory cells.Results Unexpectedly, Wnt3 was dispensable for maintenance of intestinal stem cells in mice, indicating a redundancy of Wnt signals. By contrast, cultured crypt organoids required Paneth cell-derived Wnt3. Addition of exogenous Wnt, or coculture with mesenchymal cells, restored growth of Vil-CreERT2;Wnt3fl/fl crypt organoids. Intestinal organoids from Atoh1 mutant mice did not grow or form Paneth cells; addition of Wnt3 allowed growth in the absence of Paneth cells. Wnt signaling had a synergistic effect with the Lgr4/5 ligand R-spondin to induce formation of Paneth cells. Mosaic expression of Wnt3 in organoids using a retroviral vector promoted differentiation of Paneth cells in a cell-autonomous manner.Conclusions Wnt is part of a signaling loop that affects homeostasis of intestinal stem and Paneth cells in mice. Wnt3 signaling is required for growth and development of organoid cultures, whereas nonepithelial Wnt signals could provide a secondary physiological source of Wnt.

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Crossref · 10.1053/j.gastro.2012.08.031

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  • Wnt3 expression is reduced in aged ISCs.

    “Quantitative real-time RT-PCR analyses for expression of Wnt1, 2, 2b, 3, 3a, 8a, 8b, 10a, and 10b (Farin et al., 2012) in ISCs demonstrated reduced Wnt3 (Figure 3C) levels in aged ISCs.”

    From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Farin et al., 2012

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Authors
Farin, H. F., Van Es, J. H., & Clevers, H.
Affiliations
University Medical Center Utrecht (NL)
Corresponding author
Clevers, Hans
Venue
Gastroenterology
Publisher
Elsevier BV
Published
2012-12
Volume
143
Issue
6
Pages
1518-1529.e7
ISSN
0016-5085 (ISSN-L)
OpenAlex
W2038714514
Cited by
655
References
55
Citations by year
2026: 25 · 2025: 38 · 2024: 39 · 2023: 54 · 2022: 48 · 2021: 68 · 2020: 56 · 2019: 55 · 2018: 57 · 2017: 57 · 2016: 34 · 2015: 41 · 2014: 37 · 2013: 41 · 2012: 4
FWCI
15.80
Type
journal article
Language
en
Open access
Locations
  • Gastroenterology (publishedVersion)
  • PubMed (publishedVersion)
  • KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
Funders
  • European Molecular Biology Organization
  • Top Institute Pharma
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 › Genetics › Digestive system and related health
  • Health Sciences › Medicine › Oncology › Cancer Cells and Metastasis
Keywords
Wnt signaling, Wnt3, intestinal stem cells, Paneth cells, R-spondin, Atoh1, mesenchymal cells, intestinal homeostasis
MeSH terms
Animals, Cell Differentiation, Cells, Cultured, Epithelial Cells, Homeostasis, Intestine, Small, Mice, Transgenic, Stem Cells, Signal Transduction, Paneth Cells, Models, Animal, Mice, Wnt3 Protein, In Vitro Techniques

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