A crucial role of WW45 in developing epithelial tissues in the mouse

EMBO J. 2008 Apr 23;27(8):1231-42. doi: 10.1038/emboj.2008.63. Epub 2008 Mar 27.

Abstract

The role and molecular mechanisms of a new Hippo signalling pathway are not fully understood in mammals. Here, we generated mice that lack WW45 and revealed a crucial role for WW45 in cell-cycle exit and epithelial terminal differentiation. Many organs in the mutant mouse embryos displayed hyperplasia accompanied by defects in terminal differentiation of epithelial progenitor cells owing to impaired proliferation arrest rather than intrinsic acceleration of proliferation during differentiation. Importantly, the MST1 signalling pathway is specifically activated in differentiating epithelial cells. Moreover, WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation upon differentiation signal. LATS1/2 phosphorylates YAP, which, in turn, translocates from the nucleus into the cytoplasm, resulting in cell-cycle exit and terminal differentiation of epithelial progenitor cells. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signalling in the coordinate coupling of proliferation arrest with terminal differentiation for proper epithelial tissue development in mammals.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Cycle / genetics
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / physiology*
  • Cell Differentiation / genetics
  • Cells, Cultured
  • Epithelium / embryology*
  • Epithelium / metabolism
  • Epithelium / pathology
  • Hepatocyte Growth Factor / genetics
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Protein-Serine-Threonine Kinases / metabolism
  • Protein-Serine-Threonine Kinases / physiology
  • Proto-Oncogene Proteins / genetics
  • Signal Transduction / genetics
  • Signal Transduction / physiology*

Substances

  • Cell Cycle Proteins
  • Proto-Oncogene Proteins
  • Sav1 protein, mouse
  • macrophage stimulating protein
  • Hepatocyte Growth Factor
  • Lats1 protein, mouse
  • Stk4 protein, mouse
  • Protein-Serine-Threonine Kinases