Indexed on: 18 Aug '16Published on: 18 Aug '16Published in: Hepatology
In the adult liver, the Hippo pathway kinases MST1/2 and LATS1/2 control activation of the transcriptional coactivators YAP and TAZ in hepatocytes and biliary epithelial cells (BECs) thereby regulating liver cell proliferation, differentiation and malignant transformation. Less is known about the contribution of Hippo signaling to liver development. Here we use conditional mutagenesis to show that the Hippo signaling pathway kinases LATS1 and LATS2 are redundantly required during mouse liver development to repress YAP and TAZ in both the biliary epithelial and hepatocyte lineages. In the absence of LATS1/2, BECs exhibit excess proliferation while hepatoblasts fail to mature into hepatocytes, defects that result in perinatal lethality. Using an in vitro hepatocyte differentiation assay we demonstrate that YAP activity decreases and Hippo pathway kinase activities increase upon differentiation. In addition we show that YAP activation in vitro, either resulting from depletion of its negative regulators LATS1/2 or by expression of a mutant form of YAP that is less efficiently phosphorylated by LATS1/2, results in transcriptional suppression of genes that normally accompany hepatocyte maturation. Moreover, we provide evidence that YAP activity is repressed by Hippo pathway activation upon hepatocytic maturation in vitro. Finally, we examine the localization of YAP protein during fetal liver development and find that higher levels of YAP protein are found in biliary epithelial cells, while in hepatocytes, YAP levels decrease with hepatocyte maturation.Our data indicate that Hippo signaling, mediated by the LATS1 and LATS2 kinases, is required to restrict YAP and TAZ activation during both biliary and hepatocyte differentiation and suggest that dynamic regulation of the Hippo signaling pathway plays an important role in differentiation and functional maturation of the liver. This article is protected by copyright. All rights reserved.