YAP is essential for tissue tension to ensure vertebrate 3D body shape

  • Nature volume 521, pages 217221 (14 May 2015)
  • doi:10.1038/nature14215
  • Download Citation
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Vertebrates have a unique 3D body shape in which correct tissue and organ shape and alignment are essential for function. For example, vision requires the lens to be centred in the eye cup which must in turn be correctly positioned in the head1. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force2,3. Although a century ago D’Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity4, there has been no animal model directly demonstrating how the aforementioned mechano-morphogenetic processes are coordinated to generate a body shape that withstands gravity. Here we report a unique medaka fish (Oryzias latipes) mutant, hirame (hir), which is sensitive to deformation by gravity. hir embryos display a markedly flattened body caused by mutation of YAP, a nuclear executor of Hippo signalling that regulates organ size. We show that actomyosin-mediated tissue tension is reduced in hir embryos, leading to tissue flattening and tissue misalignment, both of which contribute to body flattening. By analysing YAP function in 3D spheroids of human cells, we identify the Rho GTPase activating protein ARHGAP18 as an effector of YAP in controlling tissue tension. Together, these findings reveal a previously unrecognised function of YAP in regulating tissue shape and alignment required for proper 3D body shape. Understanding this morphogenetic function of YAP could facilitate the use of embryonic stem cells to generate complex organs requiring correct alignment of multiple tissues.

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We thank M. Raff, T. Perry, A. Ward, M. Wills, J. Caunt, J. Clarke, L. Hurst and C. Tickle for critical reading and comments. We thank M. Tada, M. Furuse, N. Wada, Y. Nakai, J. Robinson and R. Kelsh for contributions to the paper and University of Bath for fish and bioimaging facilities. This work was funded by the ERATO/SORST projects of JST, Japan (H.K.), National Institutes of Health R01EY014167 (B.A.L.) and Medical Research Council, UK (M.F.-S.).

Author information

Author notes

    • Sean Porazinski
    • , Huijia Wang
    • , Yoichi Asaoka
    • , Martin Behrndt
    •  & Tatsuo Miyamoto

    These authors contributed equally to this work.


  1. Department of Biology and Biochemistry, University of Bath, Bath BA2 7AY, UK

    • Sean Porazinski
    • , Huijia Wang
    • , Sarah Linton
    • , Atahualpa Castillo-Morales
    • , Araxi O. Urrutia
    • , Stefan Bagby
    •  & Makoto Furutani-Seiki
  2. Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan

    • Yoichi Asaoka
    • , Shoji Hata
    • , Satoshi Asaka
    •  & Hiroshi Nishina
  3. IST Austria, Am Campus 1, A-3400 Klosterneuburg, Austria

    • Martin Behrndt
    • , Hitoshi Morita
    • , S. F. Gabriel Krens
    •  & Carl-Philipp Heisenberg
  4. Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan

    • Tatsuo Miyamoto
    •  & Shinya Matsuura
  5. Department of Molecular Biology, School of Medicine, Keio University, Tokyo 160-8582, Japan

    • Takashi Sasaki
    •  & Nobuyoshi Shimizu
  6. Japan Science and Technology Agency (JST), ERATO-SORST Kondoh Differentiation Signaling Project, Kyoto 606-8305, Japan

    • Yumi Osada
    • , Akihiro Momoi
    • , Hisato Kondoh
    •  & Makoto Furutani-Seiki
  7. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA

    • Joel B. Miesfeld
    •  & Brian A. Link
  8. Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

    • Takeshi Senga
  9. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford OX3 7FY, UK

    • Hideaki Nagase
  10. Graduate School of Frontier Bioscience, Osaka University, Osaka 565-0871, Japan

    • Hisato Kondoh
  11. Faculty of Life Sciences, Kyoto Sangyo University, Kyoto 603-8555, Japan

    • Hisato Kondoh


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S.P., H.W., Y.A., M.B., T.M., H.M., S.H., T.S., S.F.G.K., Y.O., S.A., A.M., S.L., J.B.M., B.A.L., T.S., A.C.M., A.O.U., S.B. and M.F.-S. performed experiments. S.P., H.W., Y.A., M.B., T.M. and M.F.-S. conceived the study. S.B., N.S., H.N., S.M., H.K., C.-P.H., H.N. and M.F.- S. supervised the study. C.-P.H. and M.F.- S. wrote the paper. All authors interpreted data.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Hiroshi Nishina or Carl-Philipp Heisenberg or Makoto Furutani-Seiki.

Extended data

Supplementary information

PDF files

  1. 1.

    Supplementary Information

    This file contains Supplementary Tables 1-6, 2 Supplementary Discussions and Supplementary Figure 1.


  1. 1.

    Video 1: Formation of the eye by coordinated invagination of the lens and retina in WT

    Dorsal bright-field view, anterior up, between st.19 and st.23 (14 h duration). In WT, the nascent lenses and retina undergo coordinated morphogenesis to locate the lens properly in the eye.

  2. 2.

    Video 2: Dislocation of the lens in hir mutants

    Dorsal bright-field view, anterior up, between st.20 and st.24 (17 h duration). The mutant lens placodes dislocate, round up and migrate anteriorly where they loosely reattach to the retina.


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