Letter

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
Received:
Accepted:
Published online:

Abstract

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.

  • Subscribe to Nature for full access:

    $199

    Subscribe

Additional access options:

Already a subscriber?  Log in  now or  Register  for online access.

References

  1. 1.

    et al. Cdc42- and IRSp53-dependent contractile filopodia tether presumptive lens and retina to coordinate epithelial invagination. Development 136, 3657–3667 (2009)

  2. 2.

    & Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. Annu. Rev. Cell Dev. Biol. 22, 287–309 (2006)

  3. 3.

    & Mechanical control of tissue and organ development. Development 137, 1407–1420 (2010)

  4. 4.

    On Growth and Form (Cambridge Univ. Press, 1917)

  5. 5.

    et al. Neural degeneration mutants in the zebrafish, Danio rerio. Development 123, 229–239 (1996)

  6. 6.

    et al. A systematic genome-wide screen for mutations affecting organogenesis in medaka, Oryzias latipes. Mech. Dev. 121, 647–658 (2004)

  7. 7.

    et al. Characterization of the mammalian YAP (Yes-associated protein) gene and its role in defining a novel protein module, the WW domain. J. Biol. Chem. 270, 14733–14741 (1995)

  8. 8.

    The Hippo signaling pathway in development and cancer. Dev. Cell 19, 491–505 (2010)

  9. 9.

    , & The Hippo pathway in organ size control, tissue regeneration and stem cell self-renewal. Nature Cell Biol. 13, 877–883 (2011)

  10. 10.

    & Establishment of transgenic lines to monitor and manipulate Yap/Taz-Tead activity in zebrafish reveals both evolutionarily conserved and divergent functions of the Hippo pathway. Mech. Dev. 133, 177–188 (2014)

  11. 11.

    , , , & Yes-associated protein 65 (YAP) expands neural progenitors and regulates Pax3 expression in the neural plate border zone. PLoS ONE 6, e20309 (2011)

  12. 12.

    et al. TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the Hippo pathway. Mol. Cell. Biol. 28, 2426–2436 (2008)

  13. 13.

    , , , & A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP. Genes Dev. 24, 72–85 (2010)

  14. 14.

    & Forces in tissue morphogenesis and patterning. Cell 153, 948–962 (2013)

  15. 15.

    , , & Cytoskeletal motors: non-muscle myosin II takes centre stage in cell adhesion and migration. Nature Rev. Mol. Cell Biol. 10, 778–790 (2009)

  16. 16.

    , , , & Coordinated cell-shape changes control epithelial movement in zebrafish and Drosophila. Development 133, 2671–2681 (2006)

  17. 17.

    et al. Forces driving epithelial spreading in zebrafish gastrulation. Science 338, 257–260 (2012)

  18. 18.

    , , , & Aspiration of biological viscoelastic drops. Phys. Rev. Lett. 104, 218101 (2010)

  19. 19.

    , & Assembly of fibronectin extracellular matrix. Annu. Rev. Cell Dev. Biol. 26, 397–419 (2010)

  20. 20.

    , & Morphogenetic movements driving neural tube closure in Xenopus require myosin IIB. Dev. Biol. 327, 327–338 (2009)

  21. 21.

    et al. ARHGAP18, a GTPase-activating protein for RhoA, controls cell shape, spreading, and motility. Mol. Biol. Cell 22, 3840–3852 (2011)

  22. 22.

    et al. Fibronectin’s cell-adhesive domain and an amino-terminal matrix assembly domain participate in its assembly into fibroblast pericellular matrix. J. Biol. Chem. 262, 2957–2967 (1987)

  23. 23.

    , , & Diphosphorylated MRLC is required for organization of stress fibers in interphase cells and the contractile ring in dividing cells. Cell Struct. Funct. 26, 677–683 (2001)

  24. 24.

    et al. Role of YAP/TAZ in mechanotransduction. Nature 474, 179–183 (2011)

  25. 25.

    , , , & Actin depolymerization drives actomyosin ring contraction during budding yeast cytokinesis. Dev. Cell 22, 1247–1260 (2012)

  26. 26.

    et al. Modulating F-actin organization induces organ growth by affecting the Hippo pathway. EMBO J. 30, 2325–2335 (2011)

  27. 27.

    , & Extracellular matrix dynamics in development and regenerative medicine. J. Cell Sci. 121, 255–264 (2008)

  28. 28.

    et al. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol. Cell. Biol. 26, 77–87 (2006)

  29. 29.

    & The evolutionary history of YAP and the Hippo/YAP pathway. Mol. Biol. Evol. 28, 2403–2417 (2011)

  30. 30.

    Cytosystems dynamics in self-organization of tissue architecture. Nature 493, 318–326 (2013)

  31. 31.

    , & Essential techniques for introducing medaka to a zebrafish laboratory–towards the combined use of medaka and zebrafish for further genetic dissection of the function of the vertebrate genome. Methods Mol. Biol. 770, 211–241 (2011)

  32. 32.

    et al. Adhesion functions in cell sorting by mechanically coupling the cortices of adhering cells. Science 338, 253–256 (2012)

  33. 33.

    , & Single cell lineage and regionalization of cell populations during Medaka neurulation. Development 131, 2553–2563 (2004)

  34. 34.

    et al. WDR55 is a nucleolar modulator of ribosomal RNA synthesis, cell cycle progression, and teleost organ development. PLoS Genet. 4, e1000171 (2008)

  35. 35.

    et al. A medaka gene map: the trace of ancestral vertebrate proto-chromosomes revealed by comparative gene mapping. Genome Res. 14, 820–828 (2004)

  36. 36.

    , , & Involvement of ZO-1 in cadherin-based cell adhesion through its direct binding to alpha catenin and actin filaments. J. Cell Biol. 138, 181–192 (1997)

  37. 37.

    , , , & Neurons derive from the more apical daughter in asymmetric divisions in the zebrafish neural tube. Nature Neurosci. 13, 673–679 (2010)

  38. 38.

    , , , & Anisotropies in cortical tension reveal the physical basis of polarizing cortical flows. Nature 467, 617–621 (2010)

Download references

Acknowledgements

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.

Affiliations

  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

Authors

  1. Search for Sean Porazinski in:

  2. Search for Huijia Wang in:

  3. Search for Yoichi Asaoka in:

  4. Search for Martin Behrndt in:

  5. Search for Tatsuo Miyamoto in:

  6. Search for Hitoshi Morita in:

  7. Search for Shoji Hata in:

  8. Search for Takashi Sasaki in:

  9. Search for S. F. Gabriel Krens in:

  10. Search for Yumi Osada in:

  11. Search for Satoshi Asaka in:

  12. Search for Akihiro Momoi in:

  13. Search for Sarah Linton in:

  14. Search for Joel B. Miesfeld in:

  15. Search for Brian A. Link in:

  16. Search for Takeshi Senga in:

  17. Search for Atahualpa Castillo-Morales in:

  18. Search for Araxi O. Urrutia in:

  19. Search for Nobuyoshi Shimizu in:

  20. Search for Hideaki Nagase in:

  21. Search for Shinya Matsuura in:

  22. Search for Stefan Bagby in:

  23. Search for Hisato Kondoh in:

  24. Search for Hiroshi Nishina in:

  25. Search for Carl-Philipp Heisenberg in:

  26. Search for Makoto Furutani-Seiki in:

Contributions

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.

Videos

  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.

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.