The DOI matches its Crossref record; 39 of the 39 references it cites were found in a registry or an index.
Restriction of intestinal stem cell expansion and the regenerative response by YAP
Open accessAbstract
A remarkable feature of regenerative processes is their ability to halt proliferation once an organ’s structure has been restored. The Wnt signalling pathway is the major driving force for homeostatic self-renewal and regeneration in the mammalian intestine. However, the mechanisms that counterbalance Wnt-driven proliferation are poorly understood. Here we demonstrate in mice and humans that yes-associated protein 1 (YAP; also known as YAP1)—a protein known for its powerful growth-inducing and oncogenic properties—has an unexpected growth-suppressive function, restricting Wnt signals during intestinal regeneration. Transgenic expression of YAP reduces Wnt target gene expression and results in the rapid loss of intestinal crypts. In addition, loss of YAP results in Wnt hypersensitivity during regeneration, leading to hyperplasia, expansion of intestinal stem cells and niche cells, and formation of ectopic crypts and microadenomas. We find that cytoplasmic YAP restricts elevated Wnt signalling independently of the AXIN–APC–GSK-3β complex partly by limiting the activity of dishevelled (DVL). DVL signals in the nucleus of intestinal stem cells, and its forced expression leads to enhanced Wnt signalling in crypts. YAP dampens Wnt signals by restricting DVL nuclear translocation during regenerative growth. Finally, we provide evidence that YAP is silenced in a subset of highly aggressive and undifferentiated human colorectal carcinomas, and that its expression can restrict the growth of colorectal carcinoma xenografts. Collectively, our work describes a novel mechanistic paradigm for how proliferative signals are counterbalanced in regenerating tissues. Additionally, our findings have important implications for the targeting of YAP in human malignancies.
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Cites
Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche
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Paneth cells constitute the niche for Lgr5 stem cells in intestinal crypts
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YAP1 increases organ size and expands undifferentiated progenitor cells
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Self-citationTissue‐specific and inducible Cre‐mediated recombination in the gut epithelium
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Self-citation
Cited by
Zhan, T., Rindtorff, N., & Boutros, M. (2017) · Oncogene · doi:10.1038/onc.2016.304 · Cited by 2,626
Hippo pathway in organ size control, tissue homeostasis, and cancer
Yu, F.-X., Zhao, B., & Guan, K.-L. (2015) · Cell · doi:10.1016/j.cell.2015.10.044 · Cited by 2,206
YAP/TAZ at the Roots of Cancer
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Mechanisms of Hippo pathway regulation
Meng, Z., Moroishi, T., & Guan, K.-L. (2016) · Genes & Development · doi:10.1101/gad.274027.115 · Cited by 1,667
Mechanobiology of YAP and TAZ in physiology and disease
Panciera, T., Azzolin, L., Cordenonsi, M., & Piccolo, S. (2017) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm.2017.87 · Cited by 1,461
Metadata
- Authors
- Barry, E. R., Morikawa, T., Butler, B. L., Shrestha, K., de la Rosa, R., Yan, K. S., Fuchs, C. S., Magness, S. T., Smits, R., Ogino, S., Kuo, C. J., & Camargo, F. D.
- Venue
- Nature
- Published
- 2012-11-25
- Volume
- 493
- Issue
- 7430
- Pages
- 106-110
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2144283689
- Cited by
- 543
- References
- 39
- FWCI
- 16.65
- Type
- journal article
- Language
- en
- Open access
- green
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- Barry, E. R., Morikawa, T., Butler, B. L., Shrestha, K., de la Rosa, R., Yan, K. S., Fuchs, C. S., Magness, S. T., Smits, R., Ogino, S., Kuo, C. J., & Camargo, F. D. (2013). Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature. https://doi.org/10.1038/nature11693
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