A truncated beta‐catenin species promotes hepatocyte differentiation in late fetal liver development

Abstract

β-Catenin is the effector of the canonical Wnt signaling pathway with diverse roles in proliferation, adhesion, survival, and differentiation. Highly temporal regulation of Wnt signaling is reported during embryonic liver development. Here we report a novel mode of β-catenin regulation during hepatocyte differentiation. Western blots on prenatal livers reveal that while full-length β-catenin (FL-β-cat) expression decreases in concordance with decreasing hepatoblast proliferation, a 75-kDa, N-terminally truncated β-catenin (tβ-cat) accumulates as prenatal liver differentiation occurs. Immunohistochemistry and cell fractionation reveal FL-β-cat localizing to emerging bile duct cells, while tβ-cat is present in maturing hepatocytes at the membrane and the nucleus. Also, its expression correlates with that of differentiation, rather than proliferation-associated β-catenin targets. Mice with hepatoblast-specific β-catenin deficiencies die in late gestation with defects in both hepatocyte expansion and differentiation. Peptide sequencing reveals a proteolytic cleavage of the N-terminal 95 amino acids of tβ-cat, consistent with cleavage by the protease calpain. Calpain is active during the time of β-catenin truncation and its pharmacological inhibition in developing mice prevents appearance of tβ-cat. Thus we demonstrate role and regulation of a novel tβ-cat during liver development.