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Nature. 2015 May 14;521(7551):217-221. doi: 10.1038/nature14215. Epub 2015 Mar 16.

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

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Department of Biology and Biochemistry, University of Bath, Bath, BA2 7AY, UK.
Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), Tokyo 113-8510, Japan.
IST Austria, Am Campus 1, A-3400 Klosterneuburg, Austria.
Department of Genetics and Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima 734-8553, Japan.
Department of Molecular Biology, School of Medicine, Keio University, Tokyo 160-8582 Japan.
Japan Science and Technology Agency (JST), ERATO-SORST Kondoh Differentiation Signaling Project, Kyoto, 606-8305, Japan.
Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Division of Cancer Biology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Matrix Biology Section, Kennedy Institute of Rheumatology, University of Oxford, Oxford, OX3 7FY, UK.
Graduate School of Frontier Bioscience, Osaka University, Osaka 565-0871, Japan.
Contributed equally


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 head. Tissue morphogenesis depends on force generation, force transmission through the tissue, and response of tissues and extracellular matrix to force. Although a century ago D'Arcy Thompson postulated that terrestrial animal body shapes are conditioned by gravity, 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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