Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth

Chiara V. Ragni (1, 2, 3) , Nicolas Diguet (1, 2) , Jean-François Le Garrec (1, 2) , Marta Novotova (4) , Tatiana P. Resende (5) , Sorin Pop (6) , Nicolas Charon (7) , Laurent Guillemot (1) , Lisa Kitasato , Caroline Badouel (8) , Alexandre Dufour (6) , Jean-Christophe Olivo-Marin (6) , Alain Trouvé (7) , Helen Mcneill (8) , Sigolène M Meilhac (1, 2)

1 Département de Biologie du Développement et Cellules souches - Department of Developmental and Stem Cell Biology
2 BGMCD - Bases Génétiques, Moléculaires et Cellulaires du Développement
3 IFD - UPMC - Institut de Formation Doctorale
4 IMPG - Institute of Molecular Physiology and Genetics
5 Universidade do Porto = University of Porto
6 AIQ - Analyse d'Images Quantitative
7 CMLA - Centre de Mathématiques et de Leurs Applications
8 MSH - Mount Sinai Hospital [Toronto, Canada]

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.

Domaines: Embryologie et organogenèse

Chiara V. Ragni, Nicolas Diguet, Jean-François Le Garrec, Marta Novotova, Tatiana P. Resende, et al.. Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth. Nature Communications, 2017, 8, pp.14582. ⟨10.1038/ncomms14582⟩. ⟨hal-01496553⟩