YAP1 regulates cell plasticity during liver injury, regeneration and cancer, but its role in liver development is unknown. YAP1 activity was detected in biliary cells and in cells at the hepato-biliary bifurcation in single-cell RNA-sequencing analysis of developing livers. Hepatoblast deletion of Yap1 led to no impairment in Notch-driven SOX9+ ductal plate formation, but prevented the formation of the abutting second layer of SOX9+ ductal cells, blocking the formation of a patent intrahepatic biliary tree. Intriguingly, the mice survived for 8 months with severe cholestatic injury and without any hepatocyte-to-biliary transdifferentiation. Ductular reaction in the perihilar region suggested extrahepatic biliary proliferation likely seeking the missing intrahepatic biliary network. Long-term survival of these mice occurred through hepatocyte adaptation via reduced metabolic and synthetic function including altered bile acid metabolism and transport. Overall, we show YAP1 as a key regulator of bile duct development while highlighting a profound adaptive capability of hepatocytes.

中文翻译：

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由于肝祖细胞中YAP1的丢失，肝代偿性适应性肝功能永久消失

YAP1在肝损伤，再生和癌症期间调节细胞可塑性，但在肝发育中的作用尚不清楚。在发育中的肝脏的单细胞RNA序列分析中，在胆汁细胞和肝胆分叉处的细胞中检测到了YAP1活性。Yap1的成肝细胞缺失不会导致Notch驱动的SOX9 +导管板形成受损，但阻止了邻接的SOX9 +导管细胞第二层的形成，从而阻止了肝内胆管树的形成。有趣的是，这些小鼠在严重的胆汁淤积性损伤中存活了8个月，并且没有任何肝细胞到胆​​汁的转分化。肝门周围区域的导管反应提示肝外胆道增生，可能是寻找丢失的肝内胆道网络。这些小鼠的长期存活是通过降低代谢和合成功能（包括改变胆汁酸代谢和转运）而适应肝细胞而实现的。总的来说，我们显示YAP1是胆管发育的关键调节剂，同时突出了肝细胞的深远适应能力。