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

Abstract

The role and molecular mechanisms of a new Hippo signaling pathway are not fully understood in mammals. Here, we generated mice lacking WW45 and reveal a crucial role of WW45 in cell-cycle exit for epithelial terminal differentiation. Many organs in mutant embryos displayed hyperplasia accompanied by defects of terminal differentiation of epithelial cells owing to impairment of proliferation stop of epithelial cells rather than intrinsic acceleration of proliferation during differentiation. Importantly, MST1 signaling pathway is specifically activated in only differentiating epithelial cells. We also found that WW45 is required for MST1 activation and translocation to the nucleus for subsequent LATS1/2 activation, which then phosphorylate serine 127 of YAP upon differentiation signal. This phosphorylated YAP translocates from the nucleus into the cytoplasm, thereby resulting in cell-cycle exit and terminal differentiation. Collectively, these data provide compelling evidence that WW45 is a key mediator of MST1 signaling in the coordinate coupling of proliferation stop with terminal differentiation for proper epithelial tissue development in mammals.