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

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          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.

          Abstract

          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.

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          Most cited references39

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          The Hippo signaling pathway in stem cell biology and cancer.

          The Hippo signaling pathway, consisting of a highly conserved kinase cascade (MST and Lats) and downstream transcription coactivators (YAP and TAZ), plays a key role in tissue homeostasis and organ size control by regulating tissue-specific stem cells. Moreover, this pathway plays a prominent role in tissue repair and regeneration. Dysregulation of the Hippo pathway is associated with cancer development. Recent studies have revealed a complex network of upstream inputs, including cell density, mechanical sensation, and G-protein-coupled receptor (GPCR) signaling, that modulate Hippo pathway activity. This review focuses on the role of the Hippo pathway in stem cell biology and its potential implications in tissue homeostasis and cancer.
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            The Hippo pathway effectors TAZ and YAP in development, homeostasis and disease.

            Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.
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              Organogenesis and development of the liver.

              Embryonic development of the liver has been studied intensely, yielding insights that impact diverse areas of developmental and cell biology. Understanding the fundamental mechanisms that control hepatogenesis has also laid the basis for the rational differentiation of stem cells into cells that display many hepatic functions. Here, we review the basic molecular mechanisms that control the formation of the liver as an organ. Copyright (c) 2010 Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                30 June 2016
                2016
                : 7
                : 11961
                Affiliations
                [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
                Author notes
                Author information
                http://orcid.org/0000-0001-6610-1902
                Article
                ncomms11961
                10.1038/ncomms11961
                4931324
                27358050
                6931f3e3-8eb1-445d-8efc-c70d1d40af84
                Copyright © 2016, Nature Publishing Group, a division of Macmillan Publishers Limited. All Rights Reserved.

                This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 17 August 2015
                : 13 May 2016
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