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.
|Russell, Jacquelyn O; Lu, Wei-Yu; Okabe, Hirohisa et al. (2018) Hepatocyte-Specific ?-Catenin Deletion During Severe Liver Injury Provokes Cholangiocytes to Differentiate Into Hepatocytes. Hepatology :|
|Russell, Jacquelyn O; Ko, Sungjin; Saggi, Harvinder S et al. (2018) Bromodomain and Extraterminal (BET) Proteins Regulate Hepatocyte Proliferation in Hepatocyte-Driven Liver Regeneration. Am J Pathol 188:1389-1405|
|Preziosi, Morgan; Monga, Satdarshan P (2018) Novel Genetic Activation Screening in Liver Repopulation and Cancer: Now CRISPR Than Ever! Hepatology 68:408-411|
|Pradhan-Sundd, Tirthadipa; Vats, Ravi; Russell, Jacquelyn O et al. (2018) Dysregulated Bile Transporters and Impaired Tight Junctions During Chronic Liver Injury in Mice. Gastroenterology 155:1218-1232.e24|
|Zhan, Na; Michael, Adeola Adebayo; Wu, Kaiyuan et al. (2018) The Effect of Selective c-MET Inhibitor on Hepatocellular Carcinoma in the MET-Active, ?-Catenin-Mutated Mouse Model. Gene Expr 18:135-147|
|Ko, Sungjin; Monga, Satdarshan P (2018) Hepatic zonation now on hormones! Hepatology :|
|Russell, Jacquelyn O; Monga, Satdarshan P (2018) Wnt/?-Catenin Signaling in Liver Development, Homeostasis, and Pathobiology. Annu Rev Pathol 13:351-378|
|Thompson, Michael D; Moghe, Akshata; Cornuet, Pamela et al. (2018) ?-Catenin regulation of farnesoid X receptor signaling and bile acid metabolism during murine cholestasis. Hepatology 67:955-971|
|Pradhan-Sundd, Tirthadipa; Zhou, Lili; Vats, Ravi et al. (2018) Dual catenin loss in murine liver causes tight junctional deregulation and progressive intrahepatic cholestasis. Hepatology 67:2320-2337|
|Puliga, Elisabetta; Min, Qian; Tao, Junyan et al. (2017) Thyroid Hormone Receptor-? Agonist GC-1 Inhibits Met-?-Catenin-Driven Hepatocellular Cancer. Am J Pathol 187:2473-2485|
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