Da-Hye Lee1, Jae Oh Park1, Tae-Shin Kim1, Sang-Kyum Kim2, Tack-hoon Kim1, Min-chul Kim1, Gun Soo Park1, Jeong-Hwan Kim3, Shinji Kuninaka4, Eric N. Olson5, Hideyuki Saya4, Seon-Young Kim3, Ho Lee6 & Dae-Sik Lim1,*
1 National Creative Research Initiatives Center for Cell Division and Differentiation, Department of Biological Science, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea. 2 Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea. 3 Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea. 4 Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan. 5 Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390.9148, USA. 6 National Cancer Center, Graduate School of Cancer Science and Policy, Research Institute, Goyang 10408, Republic of Korea.
*Correspondence to : Dae-Sik Lim
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.