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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74 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 languageEnglish (US)
Article number11961
JournalNature communications
Volume7
DOIs
StatePublished - Jun 30 2016

ASJC Scopus subject areas

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

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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, [11961]. https://doi.org/10.1038/ncomms11961