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Cited by 196Hippo pathway signaling and YAP/TAZLiver physiology and pathologyDevelopmental Biology and Gene Regulation

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

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Lee, Da-Hye, Park, Jae Oh, Kim, Tae-Shin, Kim, Sang-Kyum, Kim, Tack-hoon, Kim, Min-chul, Park, Gun Soo, Kim, Jeong-Hwan +6 more·2016·Nature Communications
DOI 10.1038/ncomms11961PMC PMC4931324
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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.

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  • Loss of Nf2 or Lats1/2 forces hepatocytes to commit to the BEC lineage.

    “Additionally, loss of Nf2 or Lats1/2 forces hepatocytes to commit to the BEC lineage14,15.”

    From HBO1 functions as an epigenetic barrier to hepatocyte plasticity and reprogramming during liver injury (2025) · cites this paper as [14]

    The Results section, “Lats1/2 deletion triggers transition of hepatocytes to BECs” (page unavailable), reports that roughly 60% of immature BECs arose from Lats1/2-deficient hepatocytes via de-differentiation. This supports the Lats1/2 part, although “forces hepatocytes” is broader than the reported finding. The Methods mention Nf2 mice, but the passages found do not show that Nf2 loss causes this transition. (LLM, conf=0.86)

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Authors
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.
Affiliations
  • Korea Advanced Institute of Science and Technology (KR)
  • Yonsei University (KR)
  • Korea Research Institute of Bioscience and Biotechnology (KR)
  • Keio University (JP)
  • The University of Texas Southwestern Medical Center (US)
  • National Cancer Center (KR)
Corresponding author
Lim, Dae-Sik
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2016-06-30
Volume
7
Issue
1
Pages
11961-11961
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/ncomms11961
PMC
PMC4931324
OpenAlex
W2469595890
Cited by
196
References
68
Citations by year
2026: 6 · 2025: 13 · 2024: 21 · 2023: 16 · 2022: 21 · 2021: 17 · 2020: 27 · 2019: 30 · 2018: 21 · 2017: 16 · 2016: 6
FWCI
16.76
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • KRIBB Repository (submittedVersion)
  • YUHSpace (Yonsei University Medical Library) (submittedVersion, cc-by-nc-nd)
Funders
Korean Foundation for Cancer Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
Keywords
Hippo signaling pathway, YAP, TAZ, liver development, hepatoblasts, cholangiocytes, hepatocyte differentiation, TGF-beta signaling, HNF4α, LATS1/2, cell fate specification, cell proliferation, fibroblast proliferation
MeSH terms
YAP-Signaling Proteins, Acyltransferases, Animals, Animals, Newborn, Cell Differentiation, Female, Liver, Phosphoproteins, Pregnancy, Transcription Factors, Up-Regulation, Tumor Suppressor Protein p53, Transforming Growth Factor beta, Cellular Senescence, Protein Serine-Threonine Kinases, Mice, Knockout, Cell Cycle Proteins, Tumor Suppressor Proteins, Adaptor Proteins, Signal Transducing, Cell Proliferation, Mice, Hepatocyte Nuclear Factor 4, Primary Cell Culture

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