Visualization of a short-range Wnt gradient in the intestinal stem-cell niche
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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The most likely cellular source of Wnts influencing Wnt signaling upon aging is mostly Paneth cells and in part mesenchyme.
“Because it was recently reported that Wnt3 transfer requires direct cell contact and has only a very limited range (Farin et al., 2016), the most likely cellular source of Wnts that influence Wnt signaling upon aging might thus be mostly Paneth cells and, in part, mesenchyme.”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Farin et al., 2016
Wnt3 transfer requires direct cell contact and has only a very limited range.
“Because it was recently reported that Wnt3 transfer requires direct cell contact and has only a very limited range (Farin et al., 2016)”
From Canonical Wnt Signaling Ameliorates Aging of Intestinal Stem Cells (2017) · cites this paper as Farin et al., 2016
Cites
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
Sato, T., Vries, R. G., Snippert, H. J., van de Wetering, M., Barker, N., Stange, D. E., van Es, J. H., Abo, A., Kujala, P., Peters, P. J., et al. (2009) · Nature · doi:10.1038/nature07935 · Cited by 7,204 · see citing works
Self-citationIdentification of stem cells in small intestine and colon by marker gene Lgr5
Barker, N., van Es, J. H., Kuipers, J., Kujala, P., van den Born, M., Cozijnsen, M., Haegebarth, A., Korving, J., Begthel, H., Peters, P. J., et al. (2007) · Nature · doi:10.1038/nature06196 · Cited by 5,687 · see citing works
Self-citationPaneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
Sato, T., van Es, J. H., Snippert, H. J., Stange, D. E., Vries, R. G., van den Born, M., Barker, N., Shroyer, N. F., van de Wetering, M., & Clevers, H. (2011) · Nature · doi:10.1038/nature09637 · Cited by 2,510 · see citing works
Self-citationSchwank, G., Koo, B.-K., Sasselli, V., Dekkers, J. F., Heo, I., Demircan, T., Sasaki, N., Boymans, S., Cuppen, E., van der Ent, C. K., et al. (2013) · Cell Stem Cell · doi:10.1016/j.stem.2013.11.002 · Cited by 1,424 · see citing works
Self-citationSmall molecule–mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer
Chen, B., Dodge, M. E., Tang, W., Lü, J., Ma, Z., Fan, C.-W., Wei, S., Hao, W., Kilgore, J. A., Williams, N. S., et al. (2009) · Nature Chemical Biology · doi:10.1038/nchembio.137 · Cited by 1,385 · see citing works
The intestinal crypt, a prototype stem cell compartment
Clevers, H. (2013) · Cell · doi:10.1016/j.cell.2013.07.004 · Cited by 1,223 · see citing works
Self-citationTissue‐specific and inducible Cre‐mediated recombination in the gut epithelium
Marjou, F. E., Janssen, K., Chang, B. H., Li, M., Hindie, V., Chan, L., Louvard, D., Chambon, P., METZGER, D., & Robine, S. (2004) · genesis · doi:10.1002/gene.20042 · Cited by 1,044 · see citing works
Tumour suppressor RNF43 is a stem-cell E3 ligase that induces endocytosis of Wnt receptors
Koo, B., Spit, M., Jordens, I., Low, T. Y., Stange, D. E., van de Wetering, M., van Es, J. H., Mohammed, S., Heck, A. J. R., Maurice, M. M., et al. (2012) · Nature · doi:10.1038/nature11308 · Cited by 991 · see citing works
Self-citationZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner
Hao, H.-X., Xie, Y., Zhang, Y., Charlat, O., Oster, E., Avello, M., Lei, H., Mickanin, C., Liu, D., Ruffner, H., et al. (2012) · Nature · doi:10.1038/nature11019 · Cited by 974 · see citing works
CellProfiler: free, versatile software for automated biological image analysis.
Lamprecht, M. R., Sabatini, D., & Carpenter, A. E. (2007) · BioTechniques · doi:10.2144/000112257 · Cited by 964 · see citing works
Requirement for Wnt3 in vertebrate axis formation
Liu, P., Wakamiya, M., Shea, M. J., Albrecht, U., Behringer, R. R., & Bradley, A. (1999) · Nature Genetics · doi:10.1038/11932 · Cited by 900 · see citing works
Structural basis of Wnt recognition by Frizzled
Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C., & Garcia, K. (2012) · Science · doi:10.1126/science.1222879 · Cited by 880 · see citing works
Novak, A., Guo, C., Yang, W., Nagy, A., & Lobe, C. G. (2000) · genesis · doi:10.1002/1526-968x(200011/12)28:3/4 · Cited by 841 · see citing works
The Lgr5 intestinal stem cell signature: robust expression of proposed quiescent ‘+4’ cell markers
Muñoz, J., Stange, D. E., Schepers, A. G., van de Wetering, M., Koo, B., Itzkovitz, S., Volckmann, R., Kung, K. S., Köster, J., Radulescu, S., et al. (2012) · The EMBO Journal · doi:10.1038/emboj.2012.166 · Cited by 758 · see citing works
Self-citationDirect and Long-Range Action of a Wingless Morphogen Gradient
Zecca, M., Basler, K., & Struhl, G. (1996) · Cell · doi:10.1016/s0092-8674(00)81991-1 · Cited by 732 · see citing works
Redundant sources of Wnt regulate intestinal stem cells and promote formation of Paneth cells
Farin, H. F., Van Es, J. H., & Clevers, H. (2012) · Gastroenterology · doi:10.1053/j.gastro.2012.08.031 · Cited by 655 · see citing works
Self-citationExpression Pattern of Wnt Signaling Components in the Adult Intestine
Gregorieff, A., PINTO, D., Begthel, H., Destrée, O., Kielman, M. F., & Clevers, H. C. (2005) · Gastroenterology · doi:10.1016/j.gastro.2005.06.007 · Cited by 615 · see citing works
Self-citationGurney, A., Axelrod, F., Bond, C. J., Cain, J., Chartier, C., Donigan, L., Fischer, M., Chaudhari, A., Ji, M., Kapoun, A. M., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1120068109 · Cited by 614 · see citing works
Niche-independent high-purity cultures of Lgr5+ intestinal stem cells and their progeny
Yin, X., Farin, H. F., van Es, J. H., Clevers, H. C., Langer, R., & Karp, J. M. (2013) · Nature Methods · doi:10.1038/nmeth.2737 · Cited by 571 · see citing works
Self-citationKiecker, C. M., & Niehrs, C. (2001) · Development · doi:10.1242/dev.128.21.4189 · Cited by 515 · see citing works
Wnt Signaling Polarizes an Early C. elegans Blastomere to Distinguish Endoderm from Mesoderm
Thorpe, C. J., Schlesinger, A., Carter, J. C., & Bowerman, B. A. (1997) · Cell · doi:10.1016/s0092-8674(00)80530-9 · Cited by 514 · see citing works
Intestinal crypt homeostasis revealed at single-stem-cell level by in vivo live imaging
Ritsma, L., Ellenbroek, S. I. J., Zomer, A., Snippert, H. J. G., de Sauvage, F. J., Simons, B. D., Clevers, H. C., & van Rheenen, J. (2014) · Nature · doi:10.1038/nature12972 · Cited by 481 · see citing works
Self-citationWingless gradient formation in the Drosophila wing
Strigini, M., & Cohen, S. M. (2000) · Current Biology · doi:10.1016/s0960-9822(00)00378-x · Cited by 454 · see citing works
van den Heuvel, M., Nusse, R., Johnston, P., & Lawrence, P. A. (1989) · Cell · doi:10.1016/0092-8674(89)90020-2 · Cited by 444 · see citing works
Long-range action of Wingless organizes the dorsal-ventral axis of the Drosophila wing
Neumann, C. J., & Cohen, S. M. (1997) · Development · doi:10.1242/dev.124.4.871 · Cited by 428 · see citing works
Lallemand, Y., Luria, V. A., Haffner‐Krausz, R., & Lonai, P. (1998) · Transgenic Research · doi:10.1023/a:1008868325009 · Cited by 393 · see citing works
Stroma provides an intestinal stem cell niche in the absence of epithelial Wnts
Kabiri, Z., Greicius, G., Madan, B., Biechele, S., Zhong, Z. A., Zaribafzadeh, H., Edison, Aliyev, J., Wu, Y., Bunte, R. M., et al. (2014) · Development · doi:10.1242/dev.104976 · Cited by 341 · see citing works
Controlled gene expression in primary Lgr5 organoid cultures
Koo, B.-K., Stange, D. E., Sato, T., Karthaus, W., Farin, H. F., Huch, M., van Es, J. H., & Clevers, H. (2012) · Nature Methods · doi:10.1038/nmeth.1802 · Cited by 320 · see citing works
Self-citationA Localized Wnt Signal Orients Asymmetric Stem Cell Division in Vitro
Habib, S. J., Chen, B., Tsai, F., Anastassiadis, K., Meyer, T., Betzig, E., & Nusse, R. (2013) · Science · doi:10.1126/science.1231077 · Cited by 304 · see citing works
Barrow, J. R., Thomas, K. R., Boussadia, O., Moore, R. H., Kemler, R., Capecchi, M. R., & McMahon, A. P. (2003) · Genes & Development · doi:10.1101/gad.1044903 · Cited by 299 · see citing works
Patterning and growth control by membrane-tethered Wingless
Alexandre, C., Baena-López, L. A., & Vincent, J. (2013) · Nature · doi:10.1038/nature12879 · Cited by 293 · see citing works
Wnt Gradient Formation Requires Retromer Function in Wnt-Producing Cells
Coudreuse, D. Y. M., Roël, G., Betist, M. C., Destrée, O., & Korswagen, H. C. (2006) · Science · doi:10.1126/science.1124856 · Cited by 252 · see citing works
DIALIGN: multiple DNA and protein sequence alignment at BiBiServ
Morgenstern, B. (2004) · Nucleic Acids Research · doi:10.1093/nar/gkh373 · Cited by 234 · see citing works
Lgr5 intestinal stem cells have high telomerase activity and randomly segregate their chromosomes
Schepers, A. G., Vries, R., van den Born, M., van de Wetering, M., & Clevers, H. (2011) · The EMBO Journal · doi:10.1038/emboj.2011.26 · Cited by 217 · see citing works
Self-citationThe structural basis of R-spondin recognition by LGR5 and RNF43Preprint
Chen, P., Chen, X., Lin, Z., Fang, D., & He, X. L. (2013) · Genes & Development · doi:10.1101/gad.219915.113 · Cited by 175 · see citing works
Wnt Signals Can Function as Positional Cues in Establishing Cell Polarity
Goldstein, B., Takeshita, H., Mizumoto, K., & Sawa, H. (2006) · Developmental Cell · doi:10.1016/j.devcel.2005.12.016 · Cited by 163 · see citing works
Galli, L. M., Barnes, T. L., Secrest, S. S., Kadowaki, T., & Burrus, L. W. (2007) · Development · doi:10.1242/dev.02881 · Cited by 96 · see citing works
Wingless Capture by Frizzled and Frizzled2 in Drosophila Embryos
Lecourtois, M., Alexandre, C., Dubois, L., & Vincent, J. (2001) · Developmental Biology · doi:10.1006/dbio.2001.0320 · Cited by 24 · see citing works
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Nabhan, A. N., Brownfield, D., Harbury, P. B., Krasnow, M. A., & Desai, T. (2018) · Science · doi:10.1126/science.aam6603 · Cited by 731 · see citing works
Ren, J., Ding, L., Zhang, D., Shi, G., Xu, Q., Shen, S., Wang, Y., Wang, T., & Hou, Y. (2018) · Theranostics · doi:10.7150/thno.25541 · Cited by 698 · see citing works
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Başak, O., Beumer, J., Wiebrands, K., Seno, H., van Oudenaarden, A., & Clevers, H. C. (2016) · Cell stem cell · doi:10.1016/j.stem.2016.11.001 · Cited by 350 · see citing works
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Frank, D. B., Peng, T., Zepp, J. A., Snitow, M. E., Vincent, T. L., Penkala, I. J., Cui, Z., Herriges, M. J., Morley, M. P., Zhou, S., et al. (2016) · Cell Reports · doi:10.1016/j.celrep.2016.11.001 · Cited by 277 · see citing works
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Thorne, C. A., Chen, I. W., Sanman, L. E., Cobb, M. H., Wu, L. F., & Altschuler, S. J. (2018) · Developmental Cell · doi:10.1016/j.devcel.2018.01.024 · Cited by 165 · see citing works
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Ge, Y., & Fuchs, E. (2018) · Nature reviews genetics · doi:10.1038/nrg.2018.9 · Cited by 160 · see citing works
Morphogen interpretation: concentration, time, competence, and signaling dynamics
Sagner, A., & Briscoe, J. (2017) · Wiley Interdisciplinary Reviews Developmental Biology · doi:10.1002/wdev.271 · Cited by 164 · see citing works
Mechanisms of intercellular Wnt transport
Routledge, D., & Scholpp, S. (2019) · Development · doi:10.1242/dev.176073 · Cited by 146 · see citing works
Mechanistic insights into Wnt–β-catenin pathway activation and signal transduction
Maurice, M. M., & Angers, S. (2025) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-024-00823-y · Cited by 161 · see citing works
Self-citationHemodynamic Forces Sculpt Developing Heart Valves through a KLF2-WNT9B Paracrine Signaling Axis
Goddard, L. M., Duchemin, A.-L., Ramalingan, H., Wu, B., Chen, M., Bamezai, S., Yang, J., Li, L., Morley, M. P., Wang, T., et al. (2017) · Developmental Cell · doi:10.1016/j.devcel.2017.09.023 · Cited by 156 · see citing works
Paneth cells in intestinal physiology and pathophysiology
Gaßler, N. (2017) · World Journal of Gastrointestinal Pathophysiology · doi:10.4291/wjgp.v8.i4.150 · Cited by 152 · see citing works
Endothelial Wnt/β-catenin signaling reduces immune cell infiltration in multiple sclerosis
Lengfeld, J. E., Lutz, S. E., Smith, J. R., Diaconu, C., Scott, C., Kofman, S. B., Choi, C., Walsh, C. M., Raine, C. S., Agalliu, I., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1609905114 · Cited by 152 · see citing works
Integrative multi‐omics analysis of intestinal organoid differentiation
Lindeboom, R. G. H., van Voorthuijsen, L., Oost, K. C., Colman, M. J. R., Velez, M. V. L., Furlan, C., Baraille, F., Jansen, P. W. T. C., Ribeiro, A., Burgering, B. M. T., et al. (2018) · Molecular Systems Biology · doi:10.15252/msb.20188227 · Cited by 147 · see citing works
Understanding cell‐cell communication and signaling in the colorectal cancer microenvironment
AlMusawi, S., Ahmed, M., & Nateri, A. S. (2021) · Clinical and Translational Medicine · doi:10.1002/ctm2.308 · Cited by 150 · see citing works
Gli1+ Periodontium Stem Cells Are Regulated by Osteocytes and Occlusal Force
Men, Y., Wang, Y., Yi, Y., Jing, D., Luo, W., Shen, B., Stenberg, W. V., Chai, Y., Ge, W., Feng, J. Q., et al. (2020) · Developmental Cell · doi:10.1016/j.devcel.2020.06.006 · Cited by 149 · see citing works
An updated classification of hair follicle morphogenesis
Saxena, N., Mok, K., & Rendl, M. (2019) · Experimental Dermatology · doi:10.1111/exd.13913 · Cited by 147 · see citing works
Organoids in gastrointestinal diseases: From experimental models to clinical translation
Günther, C., Winner, B., Neurath, M. F., & Stappenbeck, T. S. (2022) · Gut · doi:10.1136/gutjnl-2021-326560 · Cited by 145 · see citing works
PanIN Neuroendocrine Cells Promote Tumorigenesis via Neuronal Cross-talk
Sinha, S., Fu, Y., Grimont, A., Ketcham, M., Lafaro, K. J., Saglimbeni, J. A., Askan, G., Bailey, J. M., Melchor, J. P., Zhong, Y., et al. (2017) · Cancer Research · doi:10.1158/0008-5472.can-16-0899 · Cited by 145 · see citing works
McBride, J. D., Rodriguez-Menocal, L., Guzman, W., Candanedo, A., García-Contreras, M., & Badiavas, E. V. (2017) · Stem Cells and Development · doi:10.1089/scd.2017.0087 · Cited by 141 · see citing works
Wnt5b‐associated exosomes promote cancer cell migration and proliferation
Harada, T., Yamamoto, H., Kishida, S., Kishida, M., Awada, C., Takao, T., & Kikuchi, A. (2016) · Cancer Science · doi:10.1111/cas.13109 · Cited by 130 · see citing works
Wnt/PCP controls spreading of Wnt/β-catenin signals by cytonemes in vertebrates
Mattes, B., Dang, Y., Greicius, G., Kaufmann, L. T., Prunsche, B., Rosenbauer, J., Stegmaier, J., Mikut, R., Özbek, S., Nienhaus, G. U., et al. (2018) · eLife · doi:10.7554/elife.36953 · Cited by 139 · see citing works
Glypicans shield the Wnt lipid moiety to enable signalling at a distance
McGough, I. J., Vecchia, L., Bishop, B., Malinauskas, T., Beckett, K., Joshi, D., O’Reilly, N., Siebold, C., Jones, E. Y., & Vincent, J. (2020) · Nature · doi:10.1038/s41586-020-2498-z · Cited by 139 · see citing works
SOX9 switch links regeneration to fibrosis at the single-cell level in mammalian kidneys
Aggarwal, S., Wang, Z., Pacheco, D. R. F., Rinaldi, A., Rajewski, A. C., Callemeyn, J., Loon, E. V., Lamarthée, B., Covarrubias, A. E., Hou, J., et al. (2024) · Science · doi:10.1126/science.add6371 · Cited by 136 · see citing works
A Wnt-Induced Phenotypic Switch in Cancer-Associated Fibroblasts Inhibits EMT in Colorectal Cancer
Mosa, M. H., Michels, B. E., Menche, C., Nicolas, A. M., Darvishi, T., Greten, F. R., & Farin, H. F. (2020) · Cancer Research · doi:10.1158/0008-5472.can-20-0263 · Cited by 133 · see citing works
Self-citationOrganoid-based modeling of intestinal development, regeneration, and repair
Sprangers, J., Zaalberg, I. C., & Maurice, M. M. (2020) · Cell Death and Differentiation · doi:10.1038/s41418-020-00665-z · Cited by 129 · see citing works
Self-citationLi, Y., Chen, M., Hu, J., Sheng, R., Lin, Q., He, X., & Guo, M. (2020) · Cell stem cell · doi:10.1016/j.stem.2020.09.012 · Cited by 130 · see citing works
Tales from the crypt: intestinal niche signals in tissue renewal, plasticity and cancer
Spit, M., Koo, B., & Maurice, M. M. (2018) · Open Biology · doi:10.1098/rsob.180120 · Cited by 120 · see citing works
Self-citationAge-related changes in intestinal immunity and the microbiome
Walrath, T., Dyamenahalli, K. U., Hulsebus, H. J., McCullough, R. L., Idrovo, J., Boe, D. M., McMahan, R. H., & Kovacs, E. J. (2020) · Journal of Leukocyte Biology · doi:10.1002/jlb.3ri0620-405rr · Cited by 124 · see citing works
Crystal structure of a mammalian Wnt–frizzled complex
Hirai, H., Matoba, K., Mihara, E., Arimori, T., & Takagi, J. (2019) · Nature Structural & Molecular Biology · doi:10.1038/s41594-019-0216-z · Cited by 123 · see citing works
Cancer research using organoid technology
Kretzschmar, K. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01990-z · Cited by 120 · see citing works
Advancing Intestinal Organoid Technology Toward Regenerative Medicine
Nakamura, T., & Sato, T. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.10.006 · Cited by 118 · see citing works
R-Spondin1 expands Paneth cells and prevents dysbiosis induced by graft-versus-host disease
Hayase, E., Hashimoto, D., Nakamura, K., Noizat, C., Ogasawara, R., Takahashi, S., Ohigashi, H., Yokoi, Y., Sugimoto, R., Matsuoka, S., et al. (2017) · The Journal of Experimental Medicine · doi:10.1084/jem.20170418 · Cited by 120 · see citing works
E-cadherin Beyond Structure: A Signaling Hub in Colon Homeostasis and Disease
Daulagala, A. C., Bridges, C., & Kourtidis, A. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20112756 · Cited by 119 · see citing works
The Wnt signaling pathway: a potential therapeutic target against cancer
Ghosh, N., Hossain, U., Mandal, A., & Sil, P. C. (2019) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14027 · Cited by 115 · see citing works
Wnt Signaling in 3D: Recent Advances in the Applications of Intestinal Organoids
Merenda, A., Fenderico, N., & Maurice, M. M. (2019) · Trends in Cell Biology · doi:10.1016/j.tcb.2019.10.003 · Cited by 111 · see citing works
Self-citationA ZNRF3-dependent Wnt/β-catenin signaling gradient is required for adrenal homeostasisPreprint
Basham, K. J., Rodriguez, S., Turcu, A. F., Lerário, A. M., Logan, C. Y., Rysztak, M. R., Gómez-Sánchez, C. E., Breault, D. T., Koo, B., Clevers, H. C., et al. (2019) · Genes & Development · doi:10.1101/gad.317412.118 · Cited by 112 · see citing works
Self-citationKraiczy, J., McCarthy, N., Malagola, E., Tie, G., Madha, S., Boffelli, D., Wagner, D. E., Wang, T. C., & Shivdasani, R. A. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.03.004 · Cited by 110 · see citing works
Tomić, G., Morrissey, E. R., Kozar, S., Ben‐Moshe, S., Hoyle, A., Azzarelli, R., Kemp, R., Chilamakuri, C. S. R., Itzkovitz, S., Philpott, A., et al. (2018) · Cell stem cell · doi:10.1016/j.stem.2018.07.002 · Cited by 107 · see citing works
APC controls Wnt-induced β-catenin destruction complex recruitment in human colonocytes
Parker, T. W., & Neufeld, K. L. (2020) · Scientific Reports · doi:10.1038/s41598-020-59899-z · Cited by 107 · see citing works
IL-6 Signaling Regulates Small Intestinal Crypt Homeostasis
Jeffery, V., Goldson, A. J., Dainty, J. R., Chieppa, M., & Sobolewski, A. (2017) · The Journal of Immunology · doi:10.4049/jimmunol.1600960 · Cited by 105 · see citing works
Pani, A. M., & Goldstein, B. (2018) · eLife · doi:10.7554/elife.38325 · Cited by 106 · see citing works
From single cells to tissue self‐organization
dos Santos, A. X. D. S., & Liberali, P. (2018) · FEBS Journal · doi:10.1111/febs.14694 · Cited by 102 · see citing works
Modulating Wnt signaling at the root: Porcupine and Wnt acylation
Torres, V. I., Godoy, J. A., & Inestrosa, N. C. (2019) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.02.009 · Cited by 104 · see citing works
Lymphatics and fibroblasts support intestinal stem cells in homeostasis and injury
Goto, N., Goto, S., Imada, S., Hosseini, S., Deshpande, V., & Yilmaz, Ö. H. (2022) · Cell stem cell · doi:10.1016/j.stem.2022.06.013 · Cited by 101 · see citing works
Wnt Signalling in Gastrointestinal Epithelial Stem Cells
Flanagan, D. J., Austin, C. R., Vincan, E., & Phesse, T. J. (2018) · Genes · doi:10.3390/genes9040178 · Cited by 102 · see citing works
Dclk1-expressing tuft cells: critical modulators of the intestinal niche?
Middelhoff, M. A., Westphalen, C. B., Hayakawa, Y., Yan, K. S., Gershon, M. D., Wang, T. C., & Quante, M. (2017) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.00073.2017 · Cited by 97 · see citing works
Wnt ligands influence tumour initiation by controlling the number of intestinal stem cells
Huels, D. J., Bruens, L., Hodder, M. C., Cammareri, P., Campbell, A. D., Ridgway, R. A., Gay, D. M., Solar-Abboud, M., Faller, W. J., Nixon, C., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03426-2 · Cited by 100 · see citing works
McKinley, K. L., Stuurman, N., Royer, L. A., Schartner, C., Castillo‐Azofeifa, D., Delling, M., Klein, O. D., & Vale, R. D. (2018) · eLife · doi:10.7554/elife.36739 · Cited by 95 · see citing works
Advanced 3D imaging and organoid bioprinting for biomedical research and therapeutic applications
Maharjan, S., Ma, C., Singh, B., Kang, H., Orive, G., Yao, J., & Zhang, Y. S. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115237 · Cited by 105 · see citing works
Making, Exporting, and Modulating Wnts
Langton, P. F., Kakugawa, S., & Vincent, J. (2016) · Trends in Cell Biology · doi:10.1016/j.tcb.2016.05.011 · Cited by 98 · see citing works
Inflation-collapse dynamics drive patterning and morphogenesis in intestinal organoids
Tallapragada, N. P., Cambra, H. M., Wald, T., Jalbert, S. K., Abraham, D. M., Klein, O. D., & Klein, A. M. (2021) · Cell stem cell · doi:10.1016/j.stem.2021.04.002 · Cited by 94 · see citing works
The Emerging Mechanisms of Wnt Secretion and Signaling in Development
Mehta, S., Hingole, S., & Chaudhary, V. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.714746 · Cited by 94 · see citing works
Yavitt, F. M., Kirkpatrick, B. E., Blatchley, M. R., Speckl, K. F., Mohagheghian, E., Moldovan, R., Wang, N., Dempsey, P. J., & Anseth, K. S. (2023) · Science Advances · doi:10.1126/sciadv.add5668 · Cited by 96 · see citing works
- 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
- Venue
- Nature
- Published
- 2016-02
- Volume
- 530
- Issue
- 7590
- Pages
- 340-343
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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 · 2014: 1
- 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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