Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice
Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice
复制标题
DOI：
10.1242/dev.086702
复制
发表时间：
2013-02-01
期刊：
影响因子：
4.6
通讯作者：
Kanai, Yoshiakira
中科院分区：
文献类型：
--
作者：
Uemura, Mami;Ozawa, Aisa;Kanai, Yoshiakira
先天性胆道闭锁是新生儿的一种无法治愈的疾病，遗传原因不明，导致先天性胆管和胆管系统畸形。在这里，我们发现，在小鼠器官发生过程中，SOX17在胆管和胆管上皮细胞中表达不足会导致先天性胆道闭锁和随后的急性“胚胎性肝炎”，导致围产期死亡，与C57BL/6(B6)背景小鼠中95%的Sox17杂合子新生儿相似。在胆囊和胆管发育过程中，Sox17在胆囊原基的远端边缘有表达。Sox17(+/-)B6胚胎胆囊壁上皮发育不良，部分脱离管腔壁，导致胆管狭窄或闭锁。胆囊壁上皮细胞的碎裂可能是由于Sox17(+/-)胆管/胆管上皮细胞在增殖和维持过程中的细胞自主性缺陷所致。我们的结果表明，Sox17在器官发生晚期的胆管和胆管上皮细胞的形态发生和成熟过程中起着剂量依赖性的作用，这为理解人类先天性胆道闭锁的病因和发病机制提供了一个新的切入点。
Congenital 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 similar to 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.