This timing of biliary atresia-like symptoms in mouse embryos is consistent with the hypothesis of early onset of biliary atresia in human fetuses ( Tan et al., 1994 reviewed by Davenport, 2016). In a previous study ( Uemura et al., 2013), perinatal lethality was observed in ∼90% of Sox17 heterozygous ( Sox17 +/−) mice and the embryos displayed defective development of the gallbladder including defective bile duct epithelial wall and a biliary atresia-like phenotype (an abnormal accumulation of luminal decidual cells in the bile duct), together with severe embryonic hepatitis after the first biliary excretion into the fetal duodenum at ∼16.5 days post coitum (dpc). Formation of the intrahepatic duct is regulated cooperatively by Sox9 and Sox4 ( Poncy et al., 2015), albeit that their roles in the extrahepatic duct remain unclear. The extrahepatic biliary structures (gallbladder, cystic duct, hepatic ducts and common bile duct) originate from the biliary primordium ( Spence et al., 2009 Uemura et al., 2010, 2013), which expresses SRY-box 17 ( Sox17), a core regulator of endoderm determination in mice and humans ( Tam et al., 2003). The defective gallbladder contraction positively correlated with the severity of embryonic hepatitis in Sox17 +/− embryos, suggesting a potential contribution of embryonic cholecystitis and fetal gallbladder contraction in the early pathogenesis of congenital biliary atresia. The Sox17 +/− gallbladder also showed a drastic reduction in sonic hedgehog expression, leading to aberrant smooth muscle formation and defective contraction of the fetal gallbladder. Embryonic hepatitis could be induced by conditional deletion of Sox17 in the primordial gallbladder epithelia but not in fetal liver hepatoblasts. ![]() The embryonic hepatitis showed positive correlations with the severity of cholecystitis in individual Sox17 +/− embryos. ![]() In this study, transcriptomic analyses revealed the early onset of cholecystitis in Sox17 +/− embryos, together with the appearance of ectopic cystic duct-like epithelia in their gallbladders. Sox17 haploinsufficiency causes biliary atresia-like phenotypes and hepatitis in late organogenesis mouse embryos, but the molecular and cellular mechanisms underlying this remain unclear. The gallbladder excretes cytotoxic bile acids into the duodenum through the cystic duct and common bile duct system.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |