TY - JOUR
T1 - Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth
AU - Ragni, Chiara V.
AU - Diguet, Nicolas
AU - Le Garrec, Jean François
AU - Novotova, Marta
AU - Resende, Tatiana P.
AU - Pop, Sorin
AU - Charon, Nicolas
AU - Guillemot, Laurent
AU - Kitasato, Lisa
AU - Badouel, Caroline
AU - Dufour, Alexandre
AU - Olivo-Marin, Jean Christophe
AU - Trouvé, Alain
AU - McNeill, Helen
AU - Meilhac, Sigolène M.
N1 - Publisher Copyright:
© 2017 Japan Antibiotics Research Association All rights reserved.
PY - 2017/2/27
Y1 - 2017/2/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85014245581&partnerID=8YFLogxK
U2 - 10.1038/ncomms14582
DO - 10.1038/ncomms14582
M3 - Article
C2 - 28239148
AN - SCOPUS:85014245581
SN - 2041-1723
VL - 8
JO - Nature communications
JF - Nature communications
M1 - 14582
ER -