Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth.
Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth.
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DOI：
10.1038/ncomms14582
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发表时间：
2017-02-27
影响因子：
16.6
通讯作者：
Meilhac SM
中科院分区：
文献类型：
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作者：
Ragni CV;Diguet N;Le Garrec JF;Novotova M;Resende TP;Pop S;Charon N;Guillemot L;Kitasato L;Badouel C;Dufour A;Olivo-Marin JC;Trouvé A;McNeill H;Meilhac SM
虽然在果蝇中，非典型钙粘蛋白Fat是Hippo信号传导的上游调节因子，但最接近的哺乳动物同源物Fat 4已被证明调节组织极性而不是生长。在这里，我们在小鼠心脏中显示，Fat4调节Hippo信号传导以限制生长。Fat4突变心肌更厚，心肌细胞大小和增殖增加，这是通过上调Yap1（Hippo途径的效应子）的转录活性介导的。Fat4不是典型激活Hippo激酶所必需的，但它将Yap1的伴侣Amotl1隔离在细胞核之外。Amotl1的核转位伴随着Yap1促进心肌细胞增殖。因此，我们确定Amotl1，这是不存在于苍蝇，作为一个哺乳动物的中间体非规范河马信号，下游的脂肪4。这项工作揭示了出生时心脏生长受限的机制，这一过程阻碍了哺乳动物心脏的再生潜力。哺乳动物心脏的生长是由Hippo信号控制的，但这是如何调节的尚不清楚。在这里，作者表明Fat4（一种非典型钙粘蛋白）作用于Hippo信号传导的上游，Fat4突变小鼠具有较厚的心肌，这是由支架Amot1和转录因子Yap1介导的。
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. Growth of the mammalian heart is controlled by Hippo signalling but how this is regulated is unclear. Here, the authors show that Fat4 (an atypical cadherin) acts upstream of Hippo signalling and Fat4 mutant mice have thicker myocardium, which is mediated by the scaffold Amot1 and transcription factor Yap1.