Wnt/?-catenin signaling has come to the forefront in liver biology. Its role in liver development, regeneration &stem cells is beginning to be understood. We identified its role in liver regeneration &showed activation of the Wnt/?-catenin signaling immediately after partial-hepatectomy (PHx). This was observed as nuclear translocation of ?-catenin protein ensuring G1 to S transition mediated by factors such as Cyclin-D1. In addition, we identified highest ?-catenin expression during early stages of hepatic morphogenesis in liver development &showed that its absence led to compromise in hepatoblast expansion &differentiation into bile ducts &failure of hepatocyte maturation. Recently, we have also identified the role of Wnt/?-catenin in adult liver stem cells or oval cells, where this pathway regulates their emergence &expansion. As we have uncovered several key roles of this pathway, many new questions have arisen! Several of these are of high significance &have taken the form of the current proposal, which is a competing renewal of our previously funded application (1/1/2004-12/31/2008). In the current proposal we want to focus on three aspects of liver biology-development, regeneration &hepatocyte death. We have generated ?-catenin-conditional null mice (KO1) with Foxa3-Cre driven deletion of ?-catenin in hepatoblasts during development. This strategy unveiled the importance of ?-catenin in regulating hepatoblast expansion &differentiation. We propose to identify the molecular basis by which ?-catenin is regulating these two conceptually opposing events during development &hypothesize (based on stem cell paradigm) that differential interaction of ?-catenin occurs temporally with cofactors enabling transactivation of distinct genes that regulate the two processes. We will elucidate the basis of failed biliary differentiation in absence of ?-catenin &examine how lack of ?-catenin retards hepatocyte maturation. Based on the controversy in the role of Wnt/?-catenin signaling in hepatic specification in Zebrafish &Xenopus, we will utilize KO1 to address role of ?-catenin in murine hepatic specification. We have also generated ?-catenin-conditional-null mice (KO2) using Albumin-Cre &identified lack of proliferation in these mice at 40hrs (peak proliferation in controls) after PHx. We will address the molecular signaling in the absence of ?-catenin that enables a dramatic rescue of hepatocyte proliferation at 72hrs in KO2 mice. While we are beginning to understand the role of canonical Wnt signaling, the role & extent of noncanonical pathways-Wnt/Ca2+ &planar cell polarity pathways;remain obscure &will be investigated in-depth in liver development ®eneration. Finally, based on enhanced apoptosis in hepatocytes lacking ?-catenin, we investigated Fas-&TNF?-mediated injury in the KO2. Interestingly, while KO2 mice were clearly more susceptible to Jo-2 (Fas-ligand) injury than controls, they were resistant to lipopolysaccharide (LPS)-injury. The molecular basis of these findings will be elucidated. Thus, this proposal will be a comprehensive analysis of canonical &noncanonical Wnt signaling in hepatic biology.
Understanding signaling pathways dictating the processes of liver growth, regeneration &development would be critical to identify the molecular basis of many hepatic diseases ranging from developmental anomalies to cancers &hepatic failure due to hepatitis, alcohol &other toxins. Our proposal will comprehensively examine Wnt signaling in liver biology to eventually improve prognosis of liver diseases.
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