(The) investigation of the role of Lats1/2-Yap/Taz on the lineage specification during liver development

Abstract

The Hippo pathway has emerged as tumor suppressors by regulating self-renewal and differentiation of various adult stem cells. Mice with liver specific deletion of Hippo components (Sav1, Nf2, Mst1/2) commonly develop hepatomegaly, hyperproliferation of biliary/progenitor cells and hepatomas. However, roles of Hippo signaling in the cell fate determination and differentiation during liver development are not fully understood in vivo. Here, we investigate the effects of altered endogenous Yap (Yes-associated protein) and Taz (transcriptional coactivator with PDZ-binding motif) activity by deleting both Lats1 and Lats2 (large tumor suppressor1 and 2) kinases, direct upstream regulators of Yap/Taz, on cell fate determination and properties in the liver. In embryonic liver, Yap/Taz activation by loss of Lats1/2 forces hepatoblasts to commit to biliary epithelial cells (BECs) and also to increase their proliferation, but suppresses differentiation of hepatoblasts into hepatocytes. In adult liver, acute Lats1/2 deletion in liver led to transition of hepatocytes to progenitor/biliary cells, and expansion of BECs. Of interest, oncogene Yap/Taz activation by acute Lats1/2 deletion in adult hepatocytes also induces hepatic senescent large cell changes and p53-dependent cell death. We discover that highly activated Yap/Taz suppresses hepatic differentiation via directly repressing $Hnf4\alpha$ expression. Additionally, active Yap/Taz also upregulates $Tgf\beta$ signaling, contribute to BEC differentiation, expansion of fibroblasts and suppression of hepatic differentiation. Together, our results suggest that the extents of Yap/Taz activities define cells to differentiate into which lineage of liver cells and furthermore, cells to proliferate or not in context dependent manners.