title: Sox17 haploinsufficiency results in perinatal biliary atresia and hepatitis in C57BL/6 background mice.
abstract: 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 ~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.
authors.affiliation: Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657,  Japan.
authors.forename: Mami
authors.initials: M
authors.lastname: Uemura
authors.forename: Aisa
authors.initials: A
authors.lastname: Ozawa
authors.forename: Takumi
authors.initials: T
authors.lastname: Nagata
authors.forename: Kaoruko
authors.initials: K
authors.lastname: Kurasawa
authors.forename: Naoki
authors.initials: N
authors.lastname: Tsunekawa
authors.forename: Ikuo
authors.initials: I
authors.lastname: Nobuhisa
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Taga
authors.forename: Kenshiro
authors.initials: K
authors.lastname: Hara
authors.forename: Akihiko
authors.initials: A
authors.lastname: Kudo
authors.forename: Hayato
authors.initials: H
authors.lastname: Kawakami
authors.forename: Yukio
authors.initials: Y
authors.lastname: Saijoh
authors.forename: Masamichi
authors.initials: M
authors.lastname: Kurohmaru
authors.forename: Masami
authors.initials: M
authors.lastname: Kanai-Azuma
authors.forename: Yoshiakira
authors.initials: Y
authors.lastname: Kanai
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001652:Bile Ducts / Q000378:metabolism / Q000473:pathology; D001656:Biliary Atresia / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D002779:Cholestasis / Q000235:genetics / Q000473:pathology; D004622:Embryo, Mammalian / Q000378:metabolism / Q000473:pathology; D059865:Endoplasmic Reticulum Stress; D004848:Epithelium / Q000378:metabolism / Q000473:pathology; D005260:Female; D005704:Gallbladder / Q000378:metabolism / Q000648:ultrastructure; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000235:genetics / Q000378:metabolism*; D057895:Haploinsufficiency; D006520:Hepatitis, Animal / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism; D006579:Heterozygote; D007150:Immunohistochemistry; D008099:Liver / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D011247:Pregnancy; D055760:SOXF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors
chemical_list: D024002:HMGB Proteins; D055760:SOXF Transcription Factors; C511606:Sox17 protein, mouse