FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation
FAT1 cadherin acts upstream of Hippo signalling through TAZ to regulate neuronal differentiation
复制标题
DOI：
10.1007/s00018-015-1955-6
复制
发表时间：
2015-12-01
影响因子：
8
通讯作者：
Thorne, Rick F.
中科院分区：
文献类型：
--
作者：
Ahmed, Abdulrzag F.;de Bock, Charles E.;Thorne, Rick F.
河马途径正在成为平衡祖细胞自我更新和分化的关键纽带；然而，脊椎动物河马信号传递的上游元件却知之甚少。在发育中的神经上皮细胞中Fat1钙粘附素的高表达以及在Fat1基因敲除小鼠中严重的神经学表型的表现表明了在神经发生中的作用。利用SH-SY5Y神经元分化模型和基因沉默技术，我们证明了FAT1可以控制轴突生长，也可以通过抑制增殖来驱动细胞向终末分化。FAT1的作用被证明是通过河马信号来介导的，在河马信号中，它激活了河马核心激酶成分，并拮抗了河马效应器TAZ的功能。抑制FAT1促进了TAZ的核质穿梭，导致河马靶基因CTGF的转录增强，同时伴随着Smad3核水平的增加。沉默TAZ逆转了FAT1耗竭的影响，从而将TAZ-TGFbeta信号失活与通过FAT1介导的Hippo信号联系在一起。这些发现确定FAT1是一种新的上游河马元件，调节神经细胞分化的早期阶段。
The Hippo pathway is emerging as a critical nexus that balances self-renewal of progenitors against differentiation; however, upstream elements in vertebrate Hippo signalling are poorly understood. High expression of Fat1 cadherin within the developing neuroepithelium and the manifestation of severe neurological phenotypes in Fat1-knockout mice suggest roles in neurogenesis. Using the SH-SY5Y model of neuronal differentiation and employing gene silencing techniques, we show that FAT1 acts to control neurite outgrowth, also driving cells towards terminal differentiation via inhibitory effects on proliferation. FAT1 actions were shown to be mediated through Hippo signalling where it activated core Hippo kinase components and antagonised functions of the Hippo effector TAZ. Suppression of FAT1 promoted the nucleocytoplasmic shuttling of TAZ leading to enhanced transcription of the Hippo target gene CTGF together with accompanying increases in nuclear levels of Smad3. Silencing of TAZ reversed the effects of FAT1 depletion thus connecting inactivation of TAZ-TGFbeta signalling with Hippo signalling mediated through FAT1. These findings establish FAT1 as a new upstream Hippo element regulating early stages of differentiation in neuronal cells.