β-Catenin is temporally regulated during normal liver development

Abstract

Background & Aims : β-Catenin, a key component of the Wnt pathway, plays an important role in unregulated liver growth in liver tumors, in regulated growth during liver regeneration, and in ex vivo embryonic liver cultures. Methods : We used developing livers from several stages of gestational development to examine β-catenin expression, protein-protein interactions, localization, and regulation in prenatal and postnatal livers. Results : Microarray, Northern, and protein analyses showed peak expression of β-catenin during early liver development at Embryonic day 10 (E10)-E12, followed by a decrease and a complete loss of normal β-catenin (97-kilodalton species) after E16 through the remaining prenatal period. At the early stages, β-catenin localized to the cytoplasm and nuclei of resident cells in addition to its normal membranous localization, which was seen at all later stages and in adult liver. Decreases in β-catenin levels at E14 onward coincided with its decreased gene expression and increased degradation, as seen by an increase in serine 45/threonine 41-phosphorylated β-catenin and its other negative regulators, such as axin, adenomatous polyposis coli gene product (APC), and glycogen synthase kinase-3β. Finally, we showed an intact association of E-cadherin and β-catenin despite the loss of β-catenin at E16-E18, owing to the presence of membrane-associated smaller-molecular-weight β-catenin species. Conclusions : We also identified a stage-specific expression and regulation of β-catenin during liver development that might be crucial for physiological liver development. Nuclear and cytoplasmic β-catenin corresponded to cell proliferation in liver development. Finally, a smaller-molecular-weight species of β-catenin might be maintaining normal interactions at the membrane.