LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development

Da-Hye Lee, Jae Oh Park, Tae-Shin Kim, Sang-Kyum Kim, Tack-hoon Kim, Min-chul Kim, Gun Soo Park, Jeong-Hwan Kim, Shinji Kuninaka, Eric N. Olson, Hideyuki Saya, Seon-Young Kim, Ho Lee and Dae-Sik Lim ()
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Da-Hye Lee: Korea Advanced Institute of Science and Technology
Jae Oh Park: Korea Advanced Institute of Science and Technology
Tae-Shin Kim: Korea Advanced Institute of Science and Technology
Sang-Kyum Kim: Yonsei University College of Medicine
Tack-hoon Kim: Korea Advanced Institute of Science and Technology
Min-chul Kim: Korea Advanced Institute of Science and Technology
Gun Soo Park: Korea Advanced Institute of Science and Technology
Jeong-Hwan Kim: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu
Shinji Kuninaka: Institute for Advanced Medical Research, Keio University School of Medicine
Eric N. Olson: University of Texas Southwestern Medical Center at Dallas
Hideyuki Saya: Institute for Advanced Medical Research, Keio University School of Medicine
Seon-Young Kim: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu
Ho Lee: National Cancer Center, Graduate School of Cancer Science and Policy, Research Institute
Dae-Sik Lim: Korea Advanced Institute of Science and Technology

Nature Communications, 2016, vol. 7, issue 1, 1-14

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/ncomms11961

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