LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development.
LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development.
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DOI：
10.1038/ncomms11961
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发表时间：
2016-06-30
影响因子：
16.6
通讯作者：
Lim DS
中科院分区：
文献类型：
--
作者：
Lee DH;Park JO;Kim TS;Kim SK;Kim TH;Kim MC;Park GS;Kim JH;Kuninaka S;Olson EN;Saya H;Kim SY;Lee H;Lim DS
Hippo通路调节各种成体干细胞的自我更新和分化，但其在肝脏发育过程中的细胞命运决定和分化中的作用仍不清楚。在这里，我们报告说，海马通路控制肝细胞谱系的规范和增殖，分别从Notch信号，使用小鼠和原代肝母细胞与肝脏特异性敲除的Lats1和Lats2激酶，直接上游调节雅普和TAZ。在肝脏发育期间和之后，由Lats 1/2的缺失诱导的雅普/TAZ的激活迫使成肝细胞或肝细胞定向为胆管上皮细胞（BEC）谱系。它通过上调TGF β信号传导增加BEC和成纤维细胞增殖，但通过抑制Hnf4 α表达抑制肝细胞向肝细胞的分化。值得注意的是，肝细胞中的致癌雅普/TAZ活化诱导大量p53依赖性细胞衰老/死亡。总之，我们的结果表明，雅普/TAZ活性水平以环境依赖性方式控制肝细胞分化和增殖。 Hippo通路调节干细胞和祖细胞的分化，但尚不清楚它在肝脏发育中的作用。在这里，作者敲除肝脏中的Hippo通路组分Lats1和2，导致肝细胞分化受到抑制，但促进胆管细胞分化。
The Hippo pathway regulates the self-renewal and differentiation of various adult stem cells, but its role in cell fate determination and differentiation during liver development remains unclear. Here we report that the Hippo pathway controls liver cell lineage specification and proliferation separately from Notch signalling, using mice and primary hepatoblasts with liver-specific knockout of Lats1 and Lats2 kinase, the direct upstream regulators of YAP and TAZ. During and after liver development, the activation of YAP/TAZ induced by loss of Lats1/2 forces hepatoblasts or hepatocytes to commit to the biliary epithelial cell (BEC) lineage. It increases BEC and fibroblast proliferation by up-regulating TGFβ signalling, but suppresses hepatoblast to hepatocyte differentiation by repressing Hnf4α expression. Notably, oncogenic YAP/TAZ activation in hepatocytes induces massive p53-dependent cell senescence/death. Together, our results reveal that YAP/TAZ activity levels govern liver cell differentiation and proliferation in a context-dependent manner. The Hippo pathway regulates the differentiation of stem and progenitor cells, but it is unclear how it acts in liver development. Here, the authors knockout Hippo pathway components Lats1 and 2 in the liver, causing suppression of hepatocyte differentiation but promoting biliary cell differentiation.