Publication Date:
2016-02-11
Description:
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.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉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 -- England -- Nature. 2016 Feb 18;530(7590):340-3. doi: 10.1038/nature16937. Epub 2016 Feb 10.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and University Medical Center Utrecht, 3584CT Utrecht, the Netherlands. ; German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt am Main, Germany. ; German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. ; Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584CX Utrecht, the Netherlands. ; The Maastricht Multimodal Molecular Imaging institute, Maastricht University, 6229ER Maastricht, the Netherlands. ; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario M5S 3M2, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26863187" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Animals
;
Cell Adhesion
;
Cell Division
;
Cell Membrane/*metabolism
;
Diffusion
;
Female
;
Frizzled Receptors/metabolism
;
Gene Knock-In Techniques
;
Intercellular Signaling Peptides and Proteins/metabolism
;
Intestinal Mucosa/*cytology
;
Male
;
Mice
;
Organoids/cytology/metabolism
;
Paneth Cells/cytology/metabolism
;
Receptors, G-Protein-Coupled/metabolism
;
*Stem Cell Niche
;
Stem Cells/*cytology/*metabolism
;
Ubiquitin-Protein Ligases/metabolism
;
*Wnt Signaling Pathway
;
Wnt3 Protein/genetics/*metabolism/secretion
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
Permalink
