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

Research output: Contribution to journalArticle

66 Citations (Scopus)

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 languageEnglish
Article number11961
JournalNature Communications
Volume7
DOIs
Publication statusPublished - 2016 Jun 30

Fingerprint

Long-Acting Thyroid Stimulator
liver
Liver
specifications
Specifications
Hepatocytes
Cell Proliferation
Cell Lineage
cells
Epithelial Cells
Chemical activation
activation
Adult Stem Cells
stem cells
Cell Aging
regulators
fibroblasts
Cell death
Fibroblasts
notches

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Chemistry(all)
  • Physics and Astronomy(all)

Cite this

LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. / Lee, Da Hye; Park, Jae Oh; Kim, Tae Shin; Kim, Sang Kyum; Kim, Tack Hoon; Kim, Min Chul; Park, Gun Soo; Kim, Jeong Hwan; Kuninaka, Shinji; Olson, Eric N.; Saya, Hideyuki; Kim, Seon Young; Lee, Ho; Lim, Dae Sik.

In: Nature Communications, Vol. 7, 11961, 30.06.2016.

Research output: Contribution to journalArticle

Lee, DH, Park, JO, Kim, TS, Kim, SK, Kim, TH, Kim, MC, Park, GS, Kim, JH, Kuninaka, S, Olson, EN, Saya, H, Kim, SY, Lee, H & Lim, DS 2016, 'LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development', Nature Communications, vol. 7, 11961. https://doi.org/10.1038/ncomms11961
Lee, Da Hye ; Park, Jae Oh ; Kim, Tae Shin ; Kim, Sang Kyum ; Kim, Tack Hoon ; Kim, Min Chul ; Park, Gun Soo ; Kim, Jeong Hwan ; Kuninaka, Shinji ; Olson, Eric N. ; Saya, Hideyuki ; Kim, Seon Young ; Lee, Ho ; Lim, Dae Sik. / LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development. In: Nature Communications. 2016 ; Vol. 7.
@article{e6733d1d95594a1082c9a29307633c6d,
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}",
year = "2016",
month = "6",
day = "30",
doi = "10.1038/ncomms11961",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",

}

TY - JOUR

T1 - LATS-YAP/TAZ controls lineage specification by regulating TGFβ signaling and Hnf4α expression during liver development

AU - Lee, Da Hye

AU - Park, Jae Oh

AU - Kim, Tae Shin

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.

UR - http://www.scopus.com/inward/record.url?scp=84977176795&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84977176795&partnerID=8YFLogxK

U2 - 10.1038/ncomms11961

DO - 10.1038/ncomms11961

M3 - Article

C2 - 27358050

AN - SCOPUS:84977176795

VL - 7

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

M1 - 11961

ER -