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

doi:10.1038/nature16937

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

Hubrecht Institute

Research output: Contribution to journal/periodical › Article › Scientific › peer-review

390 Citations (Scopus)

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 language	English
Pages (from-to)	340-3
Number of pages	4
Journal	Nature
Volume	530
Issue number	7590
DOIs	https://doi.org/10.1038/nature16937
Publication status	Published - 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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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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author = "Farin, {Henner F} and Ingrid Jordens and Mosa, {Mohammed H} and Onur Basak and Jeroen Korving and Tauriello, {Daniele V F} and {de Punder}, Karin and Stephane Angers and Peters, {Peter J} and Maurice, {Madelon M} and Hans Clevers",

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AU - Farin, Henner F

AU - Jordens, Ingrid

AU - Mosa, Mohammed H

AU - Basak, Onur

AU - Korving, Jeroen

AU - Tauriello, Daniele V F

AU - de Punder, Karin

AU - Angers, Stephane

AU - Peters, Peter J

AU - Maurice, Madelon M

AU - Clevers, Hans

PY - 2016/2/18

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N2 - 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.

AB - 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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KW - Animals

KW - Cell Adhesion

KW - Cell Division

KW - Cell Membrane

KW - Diffusion

KW - Female

KW - Frizzled Receptors

KW - Gene Knock-In Techniques

KW - Intercellular Signaling Peptides and Proteins

KW - Intestinal Mucosa

KW - Male

KW - Mice

KW - Organoids

KW - Paneth Cells

KW - Receptors, G-Protein-Coupled

KW - Stem Cell Niche

KW - Stem Cells

KW - Ubiquitin-Protein Ligases

KW - Wnt Signaling Pathway

KW - Wnt3 Protein

U2 - 10.1038/nature16937

DO - 10.1038/nature16937

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VL - 530

SP - 340

EP - 343

JO - Nature

JF - Nature

IS - 7590

ER -

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

Abstract

Keywords

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