Beta-catenin signaling in hepatic development and progenitors: which way does the WNT blow?

Abstract

The Wnt/β-catenin pathway is an evolutionarily conserved signaling cascade that plays key roles in development and adult tissue homeostasis and is aberrantly activated in many tumors. Over a decade of work in mouse, chick, xenopus, and zebrafish models has uncovered multiple functions of this pathway in hepatic pathophysiology. Specifically, beta-catenin, the central component of the canonical Wnt pathway, is implicated in the regulation of liver regeneration, development, and carcinogenesis. Wnt-independent activation of beta-catenin by receptor tyrosine kinases has also been observed in the liver. In liver development across various species, through regulation of cell proliferation, differentiation, and maturation, beta-catenin directs foregut endoderm specification, hepatic specification of the foregut, and hepatic morphogenesis. Its role has also been defined in adult hepatic progenitors or oval cells especially in their expansion and differentiation. Thus, beta-catenin undergoes tight temporal regulation to exhibit pleiotropic effects during hepatic development and in hepatic progenitor biology.

Fig. 1

Beta-catenin signaling plays multiple roles in liver pathophysiology. Beta-Catenin signaling regulates cellular proliferation, differentiation, survival, metabolism, and redox state. Through these events beta-catenin plays important roles in physiological processes such as liver development, regeneration, stem cell–assisted regeneration, and zonation. Beta-catenin, through regulation of metabolism, may be relevant in alcoholic liver disease (ALD), non-alcoholic fatty liver disease (NAFLD), and through its role in cell proliferation and survival plays significant roles in liver cancers.

Fig. 2

Beta-catenin signaling. A: Wnt signals through receptor frizzled and co-receptor LRP5/6 to induce inactivation of beta-catenin degradation complex comprised of Axin/APC/GSK3β/CK that enable hypophosphorylated beta-catenin to translocate to nucleus where it binds TCF/LEF and transactivates target genes. B: Beta-Catenin activation is also evident independent of Wnt signaling, through the activation of receptor tyrosine kinase (RTK) in the presence of growth factor (GF) that causes tyrosine-phosphorylation of beta-catenin and its nuclear translocation and transactivation of target genes.

Fig. 3

Temporal role and regulation of beta-catenin during prenatal hepatic development. A: In the prestreak embryo at E5.5, a gradient of Wnt activity controlled by regional expression of Wnts and Wnt antagonists (sFRP and Dkk) promotes gastrulation, with the region expressing Wnt ultimately giving rise to the anterior visceral endoderm from which the gut tube derives. B: During gut tube patterning around E8, suppression of Wnt activity through enhanced sFRP5 expression promotes hepatic competence in the ventral foregut endoderm. At this time, FGF from the developing heart and BMP signals from the septum transversum mesenchyme also contribute to hepatic competence, along with retinoic acid emanating from the lateral plate mesoderm. C: Wnt signaling resumes activity immediately after foregut patterning by E9, during which time the hepatic endodermal cells undergo a morphological transition from columnar to pseudostratified resulting in thickening into the early liver bud. In zebrafish, Wnt2bb, a downstream target of retinoic acid activity in the lateral plate mesoderm, is critical for proper timing of liver development; however, the responsible Wnt ligand in mouse has not yet been identified. D: Wnt/beta-catenin activity, in conjunction with HGF/Met activity and FGF, promotes expansion of the bipotential hepatoblasts comprising the liver bud. E: Wnt/beta-catenin activity appears to be essential for both biliary epithelial cell (BEC) differentiation and hepatocyte differentiation from hepatoblasts. While WNT activity promotes BEC differentiation, the combination of WNT + HGF appears to lead to hepatocyte differentiation.

Fig. 4

Beta-Catenin in oval cells after 15 days of DDC-exposure. Control mice fed DDC diet for 15 days, display beta-catenin (red) and A6 (green) colocalization (yellow) in oval cells (arrowhead) in liver sections by immunofluorescence. Liver sections from beta-catenin conditional null mice fed DDC diet for the same time lack beta-catenin (red) and show a dramatic decrease in numbers of A6-positive cells (green) (arrowhead).