β-catenin: a critical morphogen for gestational hepatic development.

β-Catenin is temporally expressed during early liver development. We utilized floxed β-catenin mice (lox-P sites flanking Ex2-6) & FoxA3-Cre transgenic mice to generate liver-specific β-catenin knockouts (ko). No viable offsprings were obtained with gestational lethality at around E17 stage. A significant decrease in β-catenin was observed in endodermal-derived hepatic epithelial cells in the liver after E12 by immunohistochemistry (IHC) and western blot (WB). There was a significant decrease in liver size (2-5 times) as compared to the control littermates beyond E14 stage. H&E showed decreased epithelial cells in the k.o. livers, which was confirmed by decreased numbers of E-cadherin, αFP and HNF4α-positive cells by FACS, IHC and WB. No defect in hematopoiesis was detected by the colony-forming cell unit assay. The epithelial cells from the k.o. livers failed to propagate in cultures. In addition, the hepatocytes remained undifferentiated based on histology and low glycogen, albumin & transferrin. The deficient hepatocyte compartment was due to decreased proliferation (PCNA) & survival (TUNEL). TEM studies showed epithelial cell blebbing reminiscent of oncotic death. Hepatocytes showed increased oxidative stress by MDA and 4-HNE assay secondary to decreased GSTs. Thus β-catenin is essential in normal liver development and is critical for hepatocyte maturation, expansion & survival, which are indispensable to survival. [ABSTRACT FROM AUTHOR]