title: Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth.
abstract: 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.
authors.affiliation: 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.
authors.forename: Chiara V
authors.initials: CV
authors.lastname: Ragni
authors.affiliation: Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.|CNRS URA2578, 75015 Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Diguet
authors.affiliation: Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.|CNRS URA2578, 75015 Paris, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Le Garrec
authors.affiliation: Institute of Molecular Physiology and Genetics, Centre of Biosciences, Slovak Academy of Sciences, Dúbravská cesta 9, 84005 Bratislava, Slovak Republic.
authors.forename: Marta
authors.initials: M
authors.lastname: Novotova
authors.affiliation: 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.
authors.forename: Tatiana P
authors.identifier: 0000-0002-1116-5770
authors.initials: TP
authors.lastname: Resende
authors.affiliation: Institut Pasteur, Quantitative Image Analysis Unit, 75015 Paris, France.|CNRS URA 2582, 75015 Paris, France.
authors.forename: Sorin
authors.initials: S
authors.lastname: Pop
authors.affiliation: ENS Cachan, Center of Mathematics and Their Applications, 94235 Cachan, France.|CNRS UMR 8536, 94235 Cachan, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Charon
authors.affiliation: Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Guillemot
authors.affiliation: Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.
authors.forename: Lisa
authors.initials: L
authors.lastname: Kitasato
authors.affiliation: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Caroline
authors.initials: C
authors.lastname: Badouel
authors.affiliation: Institut Pasteur, Quantitative Image Analysis Unit, 75015 Paris, France.|CNRS URA 2582, 75015 Paris, France.
authors.forename: Alexandre
authors.identifier: 0000-0002-9417-7389
authors.initials: A
authors.lastname: Dufour
authors.affiliation: Institut Pasteur, Quantitative Image Analysis Unit, 75015 Paris, France.|CNRS URA 2582, 75015 Paris, France.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Olivo-Marin
authors.affiliation: ENS Cachan, Center of Mathematics and Their Applications, 94235 Cachan, France.|CNRS UMR 8536, 94235 Cachan, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Trouvé
authors.affiliation: Samuel Lunenfeld Research Institute, Mt Sinai Hospital, Toronto, Ontario, Canada M5G 1X5.
authors.forename: Helen
authors.initials: H
authors.lastname: McNeill
authors.affiliation: Institut Pasteur, Department of Developmental and Stem Cell Biology, 75015 Paris, France.|CNRS URA2578, 75015 Paris, France.
authors.forename: Sigolène M
authors.initials: SM
authors.lastname: Meilhac
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000091304:Angiopoietin-Like Protein 1; D000818:Animals; D000831:Animals, Newborn; D015820:Cadherins / Q000378:metabolism*; D006332:Cardiomegaly / Q000235:genetics / Q000473:pathology; D018797:Cell Cycle Proteins; D049109:Cell Proliferation; D003896:Desmosomes / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008954:Models, Biological; D010750:Phosphoproteins / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D015398:Signal Transduction; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C449807:Amotl1 protein, mouse; D000091304:Angiopoietin-Like Protein 1; D015820:Cadherins; D018797:Cell Cycle Proteins; C506555:Fat4 protein, mouse; D008565:Membrane Proteins; D010750:Phosphoproteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse