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YAP triggers the Wnt/?-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury.

ABSTRACT: Impaired epithelial regeneration is a crucial pathophysiological feature of ulcerative colitis (UC). Yes-associated protein (YAP1) appears to control cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in intestinal epithelial cell (IEC) self-renewal, regeneration and tumorigenesis. We first observed that YAP was significantly reduced in 62.5% (45/72) of human UC tissues and it was dramatically enhanced during epithelial regeneration in a murine colitis model. Using lentiviral infection, we established a YAP-overexpression (YAP^WT) mouse model. We then found that after tissue injury, YAP^WT mice had increased epithelial cell self-renewal capacity and drastically restored intestinal crypt structure. Strikingly, these mice were more susceptible to colitis-associated cancer (CAC) in chemically induced carcinoma. Mechanistically, YAP and ?-catenin showed increased nuclear co-localization during regeneration after inflammation. Overexpressing YAP significantly improved IEC 'wound-healing' ability and increased the expression of both ?-catenin and the transcriptional targets of Wnt signalling Lgr5 and cyclin D1, whereas silencing ?-catenin in YAP^WT cells attenuated this effect. Remarkably, we observed that YAP could directly interact with ?-catenin in the nucleus and formed a transcriptional YAP/?-catenin/TCF4 complex; Lgr5 and cyclin D1 were confirmed to be the target genes of this complex. In contrast, cancer cell proliferation and tumour development were suppressed by the phospho-mimetic YAP mutant. In summary, nuclear YAP-driven IEC proliferation could control epithelial regeneration after inflammation and may serve as a potential therapeutic target in UC. However, excessive YAP activation promoted CAC development.

SUBMITTER: Deng F

PROVIDER: S-EPMC5833613 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury.

Deng Feihong F Peng Liang L Li Zhijun Z Tan Gao G Liang Erbo E Chen Shengbo S Zhao Xinmei X Zhi Fachao F

Cell death & disease 20180202 2

Impaired epithelial regeneration is a crucial pathophysiological feature of ulcerative colitis (UC). Yes-associated protein (YAP1) appears to control cell proliferation and differentiation. In this study, we sought to identify the roles of YAP in intestinal epithelial cell (IEC) self-renewal, regeneration and tumorigenesis. We first observed that YAP was significantly reduced in 62.5% (45/72) of human UC tissues and it was dramatically enhanced during epithelial regeneration in a murine colitis ...[more]

PMID: 29396428

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Project description:Wnt proteins modulate cell proliferation and differentiation and the self-renewal of stem cells by inducing ?-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 ?-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.

Dataset Information

YAP triggers the Wnt/?-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury.

Publications

YAP triggers the Wnt/β-catenin signalling pathway and promotes enterocyte self-renewal, regeneration and tumorigenesis after DSS-induced injury.

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