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

Henner F Farin, Ingrid Jordens, Mohammed H Mosa, Onur Basak, Jeroen Korving, Daniele V F Tauriello, Karin de Punder, Stephane Angers, Peter J Peters, Madelon M Maurice, Hans Clevers

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)340-3
Number of pages4
JournalNature
Volume530
Issue number7590
DOIs
Publication statusPublished - 18 Feb 2016

Keywords

  • Alleles
  • Animals
  • Cell Adhesion
  • Cell Division
  • Cell Membrane
  • Diffusion
  • Female
  • Frizzled Receptors
  • Gene Knock-In Techniques
  • Intercellular Signaling Peptides and Proteins
  • Intestinal Mucosa
  • Male
  • Mice
  • Organoids
  • Paneth Cells
  • Receptors, G-Protein-Coupled
  • Stem Cell Niche
  • Stem Cells
  • Ubiquitin-Protein Ligases
  • Wnt Signaling Pathway
  • Wnt3 Protein

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