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Dual role of YAP and TAZ in renewal of the intestinal epithelium

Nature Cell Biology volume 17, pages 719 (2015) | Download Citation

Abstract

The rapidly self-renewing intestinal epithelium represents an exquisite model for stem cell biology. So far, genetic studies in mice have uncovered crucial roles for several signalling pathways in the tissue. Here we show, by using intestine-specific gene transfer (iGT), that Hippo signalling effectors, YAP and TAZ, promote both the proliferation of intestinal stem/progenitor cells and their differentiation into goblet cells. These functions of YAP/TAZ are regulated by the upstream Hippo pathway kinases MST1/2 and LATS1/2. Moreover, we identify TEADs and Klf4 as partner transcription factors of YAP/TAZ in the proliferation and differentiation processes, respectively. These results indicate that Hippo signalling plays a dual role in renewal of the intestinal epithelium through the regulation of two different processes, stem/progenitor cell proliferation and differentiation into goblet cells, using two different types of transcription factor. Moreover, iGT should provide a robust platform to elucidate molecular mechanisms of intestinal epithelium self-renewal.

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Acknowledgements

We thank members of our laboratory for thoughtful discussion and helpful comments on the manuscript. This work was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan and Core Research for Evolutional Science and Technology (CREST), Japan Science and Technology (to E.N. and M.I.).

Author information

Affiliations

  1. Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan

    • Masamichi Imajo
    •  & Eisuke Nishida
  2. JST, CREST, Chiyoda-ku, Tokyo 102-0075, Japan

    • Masamichi Imajo
    •  & Eisuke Nishida
  3. Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

    • Masamichi Imajo
  4. Career-Path Promotion Unit for Young Life Scientist, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan

    • Miki Ebisuya
  5. Laboratory for Reconstitutive Developmental Biology, RIKEN Center for Developmental Biology, Kobe, Hyogo 650-0047, Japan

    • Miki Ebisuya

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Contributions

M.I. and E.N. conceived and directed the project, and prepared the manuscript. M.I. carried out most experiments. M.E. gave helpful insights and discussion.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Masamichi Imajo or Eisuke Nishida.

Integrated supplementary information

Supplementary information

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    Supplementary Information

    Supplementary Information

Excel files

  1. 1.

    Supplementary Table 1

    A list of the YAP/TAZ-dependent upregulated genes.

  2. 2.

    Supplementary Table 2

    A list of the ISC signature genes whose expression levels are decreased by the YAP/TAZ double-knockdown.

  3. 3.

    Supplementary Table 3

    Gene ontology analyses of the YAP/TAZ-dependent upregulated genes bound by YAP and/or Klf4.

  4. 4.

    Supplementary Table 4

    Statistics source data.

  5. 5.

    Supplementary Table 5

    Sequences of primers used in this study.

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DOI

https://doi.org/10.1038/ncb3084

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