Article
- The EMBO Journal (2008) 27, 1231 - 1242
- doi:10.1038/emboj.2008.63
Published online: 27 March 2008
Subject Categories:
A crucial role of WW45 in developing epithelial tissues in the mouse
Joo-Hyeon Lee1, Tae-Shin Kim1, Tae-Hong Yang1, Bon-Kyoung Koo2, Sang-Phil Oh1, Kwang-Pyo Lee1, Hyun-Jung Oh1, Sang-Hee Lee3, Young-Yun Kong2, Jin-Man Kim4 and Dae-Sik Lim1
- National Research Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon, Korea
- Division of Molecular and Life Sciences, Pohang University of Science and Technology, Kyungbuk, Korea
- Division of Electron microscopic Research, Korea Basic Science Institute, Daejeon, Korea
- Department of Pathology, College of Medicine, Chungnam National University, Daejeon, Korea
Correspondence to:
Dae-Sik Lim, National Research Laboratory, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 373-1 Guseoung-D, Yuseong-G, Daejeon 305-701, Korea. Tel.: +82 42 869 2635; Fax: +82 42 869 2610; E-mail: daesiklim@kaist.ac.kr
Received 31 October 2007; Accepted 28 February 2008
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.
Keywords:
- epithelial proliferation and differentiation,
- hWW45,
- MST1 signalling
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