WNT AND BETA-CATENIN IN HEPATIC DIFFERENTIATION: WHICH WAY DOES THE WNT BLOW?

The Wnt/beta-catenin pathway is an evolutionarily conserved signaling cascade with key roles in development and adult tissue homeostasis and is aberrantly activated in many tumors. Beta-catenin, the central component of the canonical Wnt pathway has a number of roles in liver including regulation of processes of regeneration, development and carcinogenesis. In liver development across various species, beta-catenin has been shown to undergo tight temporal regulation to modulate the processes of hepatic competence, specification and liver bud expansion through transactivation of gene targets. Conflicting observations have been reported regarding the role of beta-catenin during hepatic differentiation, however. Whereas temporal stabilization of beta-catenin in mouse hepatoblasts results in livers with excessive biliary epithelial cells (BECs) and an absence of hepatocytes, loss of beta-catenin expression in developing hepatoblasts results in failure of both BEC differentiation and hepatocyte maturation, suggesting a role for beta-catenin in promoting both processes. We now report cleavage of beta-catenin by calpain coincident with the onset of hepatocyte differentiation, generating a transcriptionally active protein that is the predominant beta-catenin species in liver until birth. The truncated beta-catenin species lacks the N-terminal 95 amino acids, is localized\ud vii\ud at the membrane and in the nucleus of differentiating hepatocytes, and correlates with expression of hepatocyte-specific beta-catenin targets (Glutamine synthetase, Regucalcin). During this time full-length beta-catenin expression is limited to developing BECs. We propose that cleavage of beta-catenin may represent a critical mechanism regulating hepatoblast cell fate, and that N-terminally truncated beta-catenin may have a unique role in hepatocyte differentiation. In addition, we found that while full-length beta-catenin was present in embryonal hepatoblastomas, the more differentiated fetal hepatoblastoma cases contain N-terminal truncations of beta-catenin. This finding may have broad implications for hepatoblastoma progression and prognosis.\ud In addition, we investigate roles for Wnt-independent activation of beta-catenin by receptor tyrosine kinases during hepatic differentiation, as well as that of non-canonical, beta-catenin-independent pathways activated by Wnt family proteins. Determining the molecular program for hepatocyte differentiation is of great clinical value not only as it relates to hepatoblastoma and other liver diseases, but also to inform efforts to create fully functional hepatocytes from various stem cell types