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; Dae Sik Lim

doi:10.1038/ncomms11961

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, Dae Sik Lim

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153 Scopus citations

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.

Original language	English (US)
Article number	11961
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11961
State	Published - Jun 30 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Lee, D. H., Park, J. O., Kim, T. S., Kim, S. K., Kim, T. H., Kim, M. C., Park, G. S., Kim, J. H., Kuninaka, S., Olson, E. N., Saya, H., Kim, S. Y., Lee, H., & Lim, D. S. (2016). LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. Nature communications, 7, Article 11961. https://doi.org/10.1038/ncomms11961

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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.",

author = "Lee, {Da Hye} and Park, {Jae Oh} and Kim, {Tae Shin} and Kim, {Sang Kyum} and Kim, {Tack Hoon} and Kim, {Min Chul} and Park, {Gun Soo} and Kim, {Jeong Hwan} and Shinji Kuninaka and Olson, {Eric N.} and Hideyuki Saya and Kim, {Seon Young} and Ho Lee and Lim, {Dae Sik}",

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AU - Lee, Da Hye

AU - Park, Jae Oh

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AU - Kim, Sang Kyum

AU - Kim, Tack Hoon

AU - Kim, Min Chul

AU - Park, Gun Soo

AU - Kim, Jeong Hwan

AU - Kuninaka, Shinji

AU - Olson, Eric N.

AU - Saya, Hideyuki

AU - Kim, Seon Young

AU - Lee, Ho

AU - Lim, Dae Sik

PY - 2016/6/30

Y1 - 2016/6/30

N2 - 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.

AB - 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.

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

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