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      Integrin signalling regulates YAP and TAZ to control skin homeostasis

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          ABSTRACT

          The skin is a squamous epithelium that is continuously renewed by a population of basal layer stem/progenitor cells and can heal wounds. Here, we show that the transcription regulators YAP and TAZ localise to the nucleus in the basal layer of skin and are elevated upon wound healing. Skin-specific deletion of both YAP and TAZ in adult mice slows proliferation of basal layer cells, leads to hair loss and impairs regeneration after wounding. Contact with the basal extracellular matrix and consequent integrin-Src signalling is a key determinant of the nuclear localisation of YAP/TAZ in basal layer cells and in skin tumours. Contact with the basement membrane is lost in differentiating daughter cells, where YAP and TAZ become mostly cytoplasmic. In other types of squamous epithelia and squamous cell carcinomas, a similar control mechanism is present. By contrast, columnar epithelia differentiate an apical domain that recruits CRB3, Merlin (also known as NF2), KIBRA (also known as WWC1) and SAV1 to induce Hippo signalling and retain YAP/TAZ in the cytoplasm despite contact with the basal layer extracellular matrix. When columnar epithelial tumours lose their apical domain and become invasive, YAP/TAZ becomes nuclear and tumour growth becomes sensitive to the Src inhibitor Dasatinib.

          Abstract

          Summary: In the squamous epithelium of the mouse skin, the transcription factors YAP and TAZ are regulated by integrin-Src signalling, and are required for proliferation of skin stem/progenitor cells.

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          Most cited references 109

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          Proteomics. Tissue-based map of the human proteome.

          Resolving the molecular details of proteome variation in the different tissues and organs of the human body will greatly increase our knowledge of human biology and disease. Here, we present a map of the human tissue proteome based on an integrated omics approach that involves quantitative transcriptomics at the tissue and organ level, combined with tissue microarray-based immunohistochemistry, to achieve spatial localization of proteins down to the single-cell level. Our tissue-based analysis detected more than 90% of the putative protein-coding genes. We used this approach to explore the human secretome, the membrane proteome, the druggable proteome, the cancer proteome, and the metabolic functions in 32 different tissues and organs. All the data are integrated in an interactive Web-based database that allows exploration of individual proteins, as well as navigation of global expression patterns, in all major tissues and organs in the human body. Copyright © 2015, American Association for the Advancement of Science.
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            Single Lgr5 stem cells build crypt-villus structures in vitro without a mesenchymal niche.

            The intestinal epithelium is the most rapidly self-renewing tissue in adult mammals. We have recently demonstrated the presence of about six cycling Lgr5(+) stem cells at the bottoms of small-intestinal crypts. Here we describe the establishment of long-term culture conditions under which single crypts undergo multiple crypt fission events, while simultanously generating villus-like epithelial domains in which all differentiated cell types are present. Single sorted Lgr5(+) stem cells can also initiate these cryptvillus organoids. Tracing experiments indicate that the Lgr5(+) stem-cell hierarchy is maintained in organoids. We conclude that intestinal cryptvillus units are self-organizing structures, which can be built from a single stem cell in the absence of a non-epithelial cellular niche.
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              Role of YAP/TAZ in mechanotransduction.

              Cells perceive their microenvironment not only through soluble signals but also through physical and mechanical cues, such as extracellular matrix (ECM) stiffness or confined adhesiveness. By mechanotransduction systems, cells translate these stimuli into biochemical signals controlling multiple aspects of cell behaviour, including growth, differentiation and cancer malignant progression, but how rigidity mechanosensing is ultimately linked to activity of nuclear transcription factors remains poorly understood. Here we report the identification of the Yorkie-homologues YAP (Yes-associated protein) and TAZ (transcriptional coactivator with PDZ-binding motif, also known as WWTR1) as nuclear relays of mechanical signals exerted by ECM rigidity and cell shape. This regulation requires Rho GTPase activity and tension of the actomyosin cytoskeleton, but is independent of the Hippo/LATS cascade. Crucially, YAP/TAZ are functionally required for differentiation of mesenchymal stem cells induced by ECM stiffness and for survival of endothelial cells regulated by cell geometry; conversely, expression of activated YAP overrules physical constraints in dictating cell behaviour. These findings identify YAP/TAZ as sensors and mediators of mechanical cues instructed by the cellular microenvironment.
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                Author and article information

                Journal
                Development
                Development
                DEV
                develop
                Development (Cambridge, England)
                The Company of Biologists Ltd
                0950-1991
                1477-9129
                15 May 2016
                15 May 2016
                : 143
                : 10
                : 1674-1687
                Affiliations
                [1 ]The Francis Crick Institute , 44 Lincoln's Inn Fields, London WC2A 3LY, UK
                [2 ]The Beatson Institute , Switchback Rd, Bearsden, Glasgow G61 1BD, UK
                [3 ]Edinburgh Cancer Research Centre, University of Edinburgh, Western General Hospital , Crewe Road South, Edinburgh EH4 2XR, UK
                Author notes
                [*]

                These authors contributed equally to this work

                []Author for correspondence ( barry.thompson@ 123456crick.ac.uk )
                Article
                DEV133728
                10.1242/dev.133728
                4874484
                26989177
                © 2016. Published by The Company of Biologists Ltd

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

                Product
                Funding
                Funded by: Wellcome Trust, http://dx.doi.org/10.13039/100004440;
                Award ID: XXXXX
                Award ID: XX
                Categories
                102
                Stem Cells and Regeneration

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