| Autor: |
Ragni CV; Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.; CNRS URA2578, 75015 Paris, France.; Sorbonne Universités, UPMC Université Paris 06, IFD, 4 Place Jussieu, 75005 Paris, France., Diguet N; Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.; CNRS URA2578, 75015 Paris, France., Le Garrec JF; Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.; CNRS URA2578, 75015 Paris, France., Novotova M; Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 84005 Bratislava, Slovak Republic., Resende TP; Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, 4200-135 Porto, Portugal.; Instituto de Engenharia Biomédica (INEB), Universidade do Porto, 4200-135 Porto, Portugal., Pop S; Institut Pasteur, Quantitative Image Analysis Unit, 75015 Paris, France.; CNRS URA 2582, 75015 Paris, France., Charon N; ENS Cachan, Center of Mathematics and Their Applications, 94235 Cachan, France.; CNRS UMR 8536, 94235 Cachan, France., Guillemot L; Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France., Kitasato L; Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France., Badouel C; Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada M5G 1X5., Dufour A; Institut Pasteur, Quantitative Image Analysis Unit, 75015 Paris, France.; CNRS URA 2582, 75015 Paris, France., Olivo-Marin JC; Institut Pasteur, Quantitative Image Analysis Unit, 75015 Paris, France.; CNRS URA 2582, 75015 Paris, France., Trouvé A; ENS Cachan, Center of Mathematics and Their Applications, 94235 Cachan, France.; CNRS UMR 8536, 94235 Cachan, France., McNeill H; Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada M5G 1X5., Meilhac SM; Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.; CNRS URA2578, 75015 Paris, France. |
| Abstrakt: |
Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart. |
