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      Asymmetric division of contractile domains couples cell positioning and fate specification

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          Abstract

          During pre-implantation development, the mammalian embryo self-organizes into the blastocyst consisting of an epithelial layer encapsulating the inner-cell mass (ICM), which gives rise to all embryonic tissues 1. In mice, oriented cell division, apico-basal polarity and acto-myosin contractility are thought to contribute to the formation of the ICM 25. However, how these processes work in concert remains unclear. Here, we show that asymmetric segregation of the apical domain generates blastomeres with different contractility, which triggers their sorting into inner and outer positions. 3D physical modeling of embryo morphogenesis reveals that cells internalize only when differences in surface contractility exceed a predictable threshold. We validate this prediction using biophysical measurements and successfully re-direct cell sorting within the developing blastocyst using maternal myosin ( Myh9) knockout chimeric embryos. Finally, we find that loss of contractility causes blastomeres to show ICM-like markers regardless of their position. In particular, contractility controls Yap sub-cellular localization 6, raising the possibility that mechanosensing occurs during blastocyst lineage specification. We conclude that contractility couples the positioning and fate specification of blastomeres. We propose that this ensures the robust self-organization of blastomeres into the blastocyst, which confers remarkable regulative capacities to mammalian embryos.

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          Most cited references 26

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          Cell adhesion. Mechanical strain induces E-cadherin-dependent Yap1 and β-catenin activation to drive cell cycle entry.

          Mechanical strain regulates the development, organization, and function of multicellular tissues, but mechanisms linking mechanical strain and cell-cell junction proteins to cellular responses are poorly understood. Here, we showed that mechanical strain applied to quiescent epithelial cells induced rapid cell cycle reentry, mediated by independent nuclear accumulation and transcriptional activity of first Yap1 and then β-catenin. Inhibition of Yap1- and β-catenin-mediated transcription blocked cell cycle reentry and progression through G1 into S phase, respectively. Maintenance of quiescence, Yap1 nuclear exclusion, and β-catenin transcriptional responses to mechanical strain required E-cadherin extracellular engagement. Thus, activation of Yap1 and β-catenin may represent a master regulator of mechanical strain-induced cell proliferation, and cadherins provide signaling centers required for cellular responses to externally applied force.
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            Expression of Cre recombinase in mouse oocytes: a means to study maternal effect genes.

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              Lifeact mice for studying F-actin dynamics.

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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                21 July 2016
                18 August 2016
                18 February 2017
                : 536
                : 7616
                : 344-348
                Affiliations
                [1 ]European Molecular Biology Laboratory, Meyerhofstrasse 1, 69117 Heidelberg, Germany
                Author notes
                [2]

                Present address: Mechanics of Mammalian Development Group, Institut Curie, CNRS UMR 3215, INSERM U934, 26, rue d’Ulm, 75248 Paris Cedex 05, France

                [3 ]Correspondence and requests for materials should be addressed to J-L.M. ( jean-leon.maitre@ 123456curie.fr ) or T.H. ( hiiragi@ 123456embl.de ).
                [5]

                Present address: Bioquant, Im Neuenheimer Feld 267, 69120 Heidelberg, Germany

                Article
                EMS69020
                10.1038/nature18958
                4998956
                27487217

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