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Restriction of intestinal stem cell expansion and the regenerative response by YAP

Abstract

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 properties1,2—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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Figure 1: YAP overabundance inhibits Wnt-mediated intestinal regeneration.
Figure 2: Loss of YAP leads to hyperactive Wnt signalling and expansion of the stem cell niche after injury or stimulation with Rspo1.
Figure 3: YAP restricts Wnt signalling by blocking DVL nuclear translocation.
Figure 4: YAP function in human colorectal cancer.

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Primary accessions

Gene Expression Omnibus

Data deposits

Microarray data have been deposited in the Gene Expression Omnibus database under accession number GSE41509.

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Acknowledgements

We thank L. Zon and Camargo laboratory members for critical review of this manuscript and X. He for Myc–DVL2 constructs. This work was supported by grants from the Stand Up to Cancer-AACR initiative (F.D.C.), National Institutes of Health R01 CA131426 and AR064036 (F.D.C.) and the Harvard Stem Cell Institute (F.D.C.). F.D.C. is a Pew Scholar in the Biomedical Sciences. E.R.B. is supported by a postdoctoral fellowship from the American Cancer Society Illinois Division (PF-12-245-01-CCG). This work has also benefited from support to K.S.Y. (CIRM, and 1K08DK096048), C.J.K. (1U01DK085527), S.O. (R01 CA151993 and R01 DK091427), S.T.M. (P01CA87969) and C.S.F. (P50CA127003).

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Authors and Affiliations

Authors

Contributions

E.R.B. and F.D.C. designed the study. E.R.B., B.L.B., K.S., R.d.l.R. and S.T.M. performed experiments. T.M. performed immunohistochemistry and analysis of human tumour samples. K.S.Y., C.S.F., R.S., S.O. and C.J.K. provided reagents for the study.

Corresponding author

Correspondence to Fernando D. Camargo.

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The authors declare no competing financial interests.

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This file contains Supplementary Figures 1-11. (PDF 11027 kb)

Supplementary Data

This file contains Supplementary Table 1 with genes identified in microarrays as being misregulated. (XLS 247 kb)

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Barry, E., Morikawa, T., Butler, B. et al. Restriction of intestinal stem cell expansion and the regenerative response by YAP. Nature 493, 106–110 (2013). https://doi.org/10.1038/nature11693

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