Embryonic cholecystitis and defective gallbladder contraction in the <i>Sox17</i>-haploinsufficient mouse model of biliary atresia

Abstract

The gallbladder excretes cytotoxic bile acids into the duodenum through the cystic duct and common bile duct system. <i>Sox17</i> haploinsufficiency causes biliary atresia-like phenotypes and hepatitis in late organogenesis mouse embryos, but the molecular and cellular mechanisms underlying this remain unclear. In this study, transcriptomic analyses revealed the early onset of cholecystitis in <i>Sox17</i>^+/- embryos, together with the appearance of ectopic cystic duct-like epithelia in their gallbladders. The embryonic hepatitis showed positive correlations with the severity of cholecystitis in individual <i>Sox17</i>^+/- embryos. Embryonic hepatitis could be induced by conditional deletion of <i>Sox17</i> in the primordial gallbladder epithelia but not in fetal liver hepatoblasts. The <i>Sox17</i>^+/- gallbladder also showed a drastic reduction in sonic hedgehog expression, leading to aberrant smooth muscle formation and defective contraction of the fetal gallbladder. The defective gallbladder contraction positively correlated with the severity of embryonic hepatitis in <i>Sox17</i>^+/- embryos, suggesting a potential contribution of embryonic cholecystitis and fetal gallbladder contraction in the early pathogenesis of congenital biliary atresia.