Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice

Abstract

SUMMARYCongenital biliary atresia is an incurable disease of newborn infants, of unknown genetic causes, that results in congenital deformation of the gallbladder and biliary duct system. Here, we show that during mouse organogenesis, insufficient SOX17 expression in the gallbladder and bile duct epithelia results in congenital biliary atresia and subsequent acute 'embryonic hepatitis', leading to perinatal death in ~95% of the Sox17 heterozygote neonates in C57BL/6 (B6) background mice. During gallbladder and bile duct development, Sox17 was expressed at the distal edge of the gallbladder primordium. In the Sox17 +/-B6 embryos, gallbladder epithelia were hypoplastic, and some were detached from the luminal wall, leading to bile duct stenosis or atresia. The shredding of the gallbladder epithelia is probably caused by cell-autonomous defects in proliferation and maintenance of the Sox17 +/-gallbladder/bile duct epithelia. Our results suggest that Sox17 plays a dosage-dependent function in the morphogenesis and maturation of gallbladder and bile duct epithelia during the late-organogenic stages, highlighting a novel entry point to the understanding of the etiology and pathogenesis of human congenital biliary atresia.

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

“…1E). Considering our previous observation of hypoplasia and deciduation in the Sox17 +/− gallbladder epithelia (Uemura et al, 2013), these data suggest that the gallbladder epithelial cells might be replaced with the ectopic SOX9-positive cystic duct-like epithelial cells. In addition, such elevated expression of Sox9 in the Sox17 +/− gallbladder correlates with the subsequent expression of Sox4, which can act redundantly with Sox9 in intrahepatic duct formation (Poncy et al, 2015) (Fig.…”

“…The Sox17 +/− gallbladder shows severe hypotrophy and a single-layered cuboidal epithelium with few epithelial folds (Fig. 1A) (see also Uemura et al, 2013), similar in appearance to the cystic duct epithelia of wild-type embryos at the same stage (17.5 dpc). This is consistent with morphometric data showing a significant reduction in epithelial height, cavity and/or epithelial area of the Sox17 +/− gallbladder, such that these values are similar to those of wild-type cystic ducts (Fig.…”

“…To examine the transcriptomic changes in the Sox17 +/− gallbladder, microarray analyses were conducted using gallbladder (distal) and cystic duct (proximal) segments of the Sox17 +/− and wild-type gallbladder primordia at 15.5 dpc, before the first secretion of bile fluid from the fetal liver (Uemura et al, 2013) (Fig. 2A,B).…”

“…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. 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). 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).…”

“…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, 2010Uemura et al, , 2013, which expresses SRY-box 17 (Sox17), a core regulator of endoderm determination in mice and humans (Tam et al, 2003). 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.…”