Tu2015 Par1a/B Regulates Jag1 Expression and Bile Duct Development in Mice

Abstract

Background: Partitioning defective (Par) 1a/b are members of a family apico-basal polarity proteins. Par1a/b contribute to epithelial cell-cell adhesion and morphogenesis in vitro. They are functionally redundant serine-threonine kinases that may compensate for each other in vivo. Complete loss of Par1 a/b leads to death early in embryogenesis, prior to liver development, while mice with only one out of four alleles, Par 1a -/-: Par 1b +/(Par1a/b KH) and Par 1a +/-: Par 1b -/(Par 1a/b HK) die postnatally. Par 1a/b HK and HK kidneys are hypoplastic with abnormal proximal tubules associated with decreased Jagged-1 expression. Alterations in signaling in the Jagged-1/Notch-2 pathways have been associated with several types of biliary tract abnormalities, including Alagelle's Syndrome and biliary atresia. Hypothesis: Par1a/b contributes to hepatic bile duct epithelial development. Results: We examined the time-course of Par 1a/b in embryonic and adult livers using western blotting and immunostaining. Par 1a/b are expressed throughout liver development (E16-E18) and are expressed in adult bile ducts. Next, to examine the role of Par1a/b in liver epithelial development, Par 1a/b HH mice underwent timed matings. Bile duct development was examined in E18 and newborn mice by light microscopy and immunostaining with cytokeratin 8 and 19 and Rhodamine DBA. While littermates had readily identifiable bile ducts around portal veins, Par1a/b KH livers had decreased bile ducts, and Par1a/b HK mice lacked bile duct development. Decreased Jag1 expression was identified in Par1a/b KH and HK livers. Conclusions: Par 1a/b are expressed in the developing liver and are required for bile duct development in mice, likely via effects on Jag1 expression. Ongoing experiments are examining the interaction of Par1a/b and Notch signaling in the developing liver.