β-catenin antisense studies in embryonic liver cultures: Role in proliferation, apoptosis, and lineage specification

Background & Aims: Wnt/β-catenin pathway activation occurs during liver growth in hepatoblastomas, hepatocellular cancers, and liver regeneration. The aim of this study was to investigate the role of β-catenin, a key component of the Wnt pathway, in liver development as well as its normal distribution in developing liver. Methods: Embryonic liver cultures and β-catenin antisense phosphorodiamidate morpholino oligomer (PMO) were used to elucidate the role of β-catenin in liver development. Livers from embryos at 10 days of gestational development were cultured in the presence of antisense or control PMO for 72 hours and analyzed. Results: β-Catenin shows stage-specific localization and distinct distribution compared with known markers in developing liver. A substantial decrease in β-catenin protein was evident in the organs cultured in the presence of antisense. β-Catenin inhibition decreased cell proliferation and increased apoptosis in these organ cultures. Presence of antisense resulted in loss of CK19 immunoreactivity of the bipotential stem cells. β-Catenin inhibition also promoted c-kit immunoreactivity of the hepatocytes. Conclusions: We conclude that the PMO antisense to β-catenin effectively inhibits synthesis of its protein. β-Catenin modulates cell proliferation and apoptosis in developing liver. It may play a significant role in early biliary lineage commitment of the bipotential stem cells and also seems to be important in hepatocyte maturation. GASTROENTEROLOGY 2003;124:202-216