Surrogate Wnt agonists that phenocopy canonical Wnt and β-catenin signalling
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Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing β-catenin-dependent signalling through the Wnt receptor frizzled (FZD) and the co-receptors LRP5 and LRP6 to regulate cell fate decisions and the growth and repair of several tissues. The 19 mammalian Wnt proteins are cross-reactive with the 10 FZD receptors, and this has complicated the attribution of distinct biological functions to specific FZD and Wnt subtype interactions. Furthermore, Wnt proteins are modified post-translationally by palmitoylation, which is essential for their secretion, function and interaction with FZD receptors. As a result of their acylation, Wnt proteins are very hydrophobic and require detergents for purification, which presents major obstacles to the preparation and application of recombinant Wnt proteins. This hydrophobicity has hindered the determination of the molecular mechanisms of Wnt signalling activation and the functional importance of FZD subtypes, and the use of Wnt proteins as therapeutic agents. Here we develop surrogate Wnt agonists, water-soluble FZD-LRP5/LRP6 heterodimerizers, with FZD5/FZD8-specific and broadly FZD-reactive binding domains. Similar to WNT3A, these Wnt agonists elicit a characteristic β-catenin signalling response in a FZD-selective fashion, enhance the osteogenic lineage commitment of primary mouse and human mesenchymal stem cells, and support the growth of a broad range of primary human organoid cultures. In addition, the surrogates can be systemically expressed and exhibit Wnt activity in vivo in the mouse liver, regulating metabolic liver zonation and promoting hepatocyte proliferation, resulting in hepatomegaly. These surrogates demonstrate that canonical Wnt signalling can be activated by bi-specific ligands that induce receptor heterodimerization. Furthermore, these easily produced, non-lipidated Wnt surrogate agonists facilitate functional studies of Wnt signalling and the exploration of Wnt agonists for translational applications in regenerative medicine.
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Kretzschmar, K. (2021) · Journal of Molecular Medicine · doi:10.1007/s00109-020-01990-z · Cited by 120 · see citing works
Hu, S., Liu, S., Bian, Y., Poddar, M., Singh, S., Cao, C., McGaughey, J., Bell, A., Blazer, L. L., Adams, J. J., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100754 · Cited by 118 · see citing works
Laksitorini, M. D., Yathindranath, V., Xiong, W., Hombach-Klonisch, S., & Miller, D. W. (2019) · Scientific Reports · doi:10.1038/s41598-019-56075-w · Cited by 105 · see citing works
<i>WNT10A</i> , dermatology and dentistry
Doolan, B. J., Onoufriadis, A., Kantaputra, P., & McGrath, J. A. (2021) · British Journal of Dermatology · doi:10.1111/bjd.20601 · Cited by 56 · see citing works
Tissue-targeted R-spondin mimetics for liver regeneration
Zhang, Z., Broderick, C., Nishimoto, M., Yamaguchi, T., Lee, S.-J., Zhang, H., Chen, H., Patel, M., Ye, J., Ponce, A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-70912-3 · Cited by 50 · see citing works
Mouse liver assembloids model periportal architecture and biliary fibrosis
Dowbaj, A. M., Sljukic, A., Niksic, A., Landerer, C., Delpierre, J., Yang, H., Lahree, A., Kühn, A. C., Beers, D., Byrne, H. M., et al. (2025) · Nature · doi:10.1038/s41586-025-09183-9 · Cited by 40 · see citing works
Primary cilia promote the differentiation of human neurons through the WNT signaling pathway
Coschiera, A., Yoshihara, M., Lauter, G., Ezer, S., Pucci, M., Li, H., Kavšek, A., Riedel, C. G., Kere, J., & Swoboda, P. (2024) · BMC Biology · doi:10.1186/s12915-024-01845-w · Cited by 26 · see citing works
- Authors
- Janda, C. Y., Dang, L. T., You, C., Chang, J., de Lau, W., Zhong, Z. A., Yan, K. S., Marecic, O., Siepe, D., Li, X., Moody, J. D., Williams, B. O., Clevers, H., Piehler, J., Baker, D., Kuo, C. J., & Garcia, K. C.
- Affiliations
- Howard Hughes Medical Institute (US)
- Osnabrück University (DE)
- Stanford Medicine (US)
- Van Andel Institute (US)
- Royal Netherlands Academy of Arts and Sciences (NL)
- ORCID
- Venue
- Nature
- Published
- 2017-05
- Volume
- 545
- Issue
- 7653
- Pages
- 234-237
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5815871
- OpenAlex
- W2610869016
- Cited by
- 403
- References
- 73
- Citations by year
- 2026: 35 · 2025: 39 · 2024: 57 · 2023: 49 · 2022: 55 · 2021: 53 · 2020: 47 · 2019: 30 · 2018: 29 · 2017: 8
- FWCI
- 12.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- KNAW Research Portal (The Royal Netherlands Academy of Arts and Sciences) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- KNAW research portal (Royal Academy of Art and Sciences (KNAW)) (submittedVersion)
- Utrecht University Repository (Utrecht University) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (40-41400-98-1108)
- National Cancer Institute (U01CA176299, U01CA217851)
- National Institute of General Medical Sciences (R01GM097015, T32GM007266)
- National Institute of Allergy and Infectious Diseases (U19AI116484)
- National Institute of Diabetes and Digestive and Kidney Diseases (U24DK085532, U01DK085527, K08DK096048, U01DK085532)
- 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 › Hedgehog Signaling Pathway Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Wnt/β-catenin signaling, β-catenin signaling, Frizzled receptors, intestinal organoids, liver regeneration, Wnt3, osteogenic differentiation, R-spondin, Lgr5+ intestinal stem cells, palmitoylation, stem cell self-renewal
- MeSH terms
- Animals, Cell Differentiation, Hepatomegaly, Humans, Intestines, Ligands, Liver, Models, Molecular, Organoids, Solubility, Signal Transduction, Cell Lineage, Hepatocytes, Tissue Culture Techniques, Cell Proliferation, Wnt Proteins, Frizzled Receptors, beta Catenin, Mice, Protein Multimerization, HEK293 Cells, Hydrophobic and Hydrophilic Interactions, Mesenchymal Stem Cells, Wnt Signaling Pathway, Low Density Lipoprotein Receptor-Related Protein-6, Low Density Lipoprotein Receptor-Related Protein-5
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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