title: LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development.
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.
authors.affiliation: 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.
authors.forename: Da-Hye
authors.initials: DH
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Jae Oh
authors.initials: JO
authors.lastname: Park
authors.affiliation: 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.
authors.forename: Tae-Shin
authors.initials: TS
authors.lastname: Kim
authors.affiliation: Department of Pathology, Yonsei University College of Medicine, Seoul 03722, Republic of Korea.
authors.forename: Sang-Kyum
authors.initials: SK
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Tack-Hoon
authors.initials: TH
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Min-Chul
authors.initials: MC
authors.lastname: Kim
authors.affiliation: 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.
authors.forename: Gun Soo
authors.initials: GS
authors.lastname: Park
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
authors.forename: Jeong-Hwan
authors.initials: JH
authors.lastname: Kim
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuninaka
authors.affiliation: Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-8582, Japan.
authors.forename: Hideyuki
authors.identifier: 0000-0001-6610-1902
authors.initials: H
authors.lastname: Saya
authors.affiliation: Medical Genomics Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong-gu, Daejeon 34141, Republic of Korea.
authors.forename: Seon-Young
authors.initials: SY
authors.lastname: Kim
authors.affiliation: National Cancer Center, Graduate School of Cancer Science and Policy, Research Institute, Goyang 10408, Republic of Korea.
authors.forename: Ho
authors.initials: H
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Dae-Sik
authors.initials: DS
authors.lastname: Lim
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D018797:Cell Cycle Proteins; D002454:Cell Differentiation; D049109:Cell Proliferation; D016922:Cellular Senescence; D005260:Female; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism; D008099:Liver / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000378:metabolism*; D011247:Pregnancy; D061251:Primary Cell Culture; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000502:physiology*; D015854:Up-Regulation; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D010750:Phosphoproteins; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; C490501:Lats1 protein, mouse; C522633:LATS2 protein, mouse; D017346:Protein Serine-Threonine Kinases