{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T21:42:02Z","timestamp":1773178922757,"version":"3.50.1"},"reference-count":46,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:00:00Z","timestamp":1579824000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2020,1,24]],"date-time":"2020-01-24T00:00:00Z","timestamp":1579824000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2020,4]]},"abstract":"\n Background and Aims<\/jats:title>\n Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily by haploinsufficiency of the Notch ligand jagged1. The course of the liver disease is highly variable in ALGS. However, the genetic basis for ALGS phenotypic variability is unknown. Previous studies have reported decreased expression of the transcription factor SOX9 (sex determining region Y\u2010box 9) in late embryonic and neonatal livers of Jag1<\/jats:italic>\u2010deficient mice. Here, we investigated the effects of altering the Sox9<\/jats:italic> gene dosage on the severity of liver disease in an ALGS mouse model.<\/jats:p>\n <\/jats:sec>\n \n Approach and Results<\/jats:title>\n Conditional removal of one copy of Sox9<\/jats:italic> in Jag1+\/\u2212\n <\/jats:italic> livers impairs the biliary commitment of cholangiocytes and enhances the inflammatory reaction and liver fibrosis. Loss of both copies of Sox9<\/jats:italic> in Jag1+\/\u2212\n <\/jats:italic> livers further worsens the phenotypes and results in partial lethality. Ink injection experiments reveal impaired biliary tree formation in the periphery of P30 Jag1+\/\u2212\n <\/jats:italic> livers, which is improved by 5\u00a0months of age. Sox9<\/jats:italic> heterozygosity worsens the P30 biliary tree phenotype and impairs the partial recovery in 5\u2010month\u2010old animals. Notably, Sox9<\/jats:italic> overexpression improves BD paucity and liver phenotypes in Jag1+\/\u2212\n <\/jats:italic> mice without ectopic hepatocyte\u2010to\u2010cholangiocyte transdifferentiation or long\u2010term liver abnormalities. Notch2<\/jats:italic> expression in the liver is increased following Sox9<\/jats:italic> overexpression, and SOX9 binds the Notch2<\/jats:italic> regulatory region in the liver. Histological analysis shows a correlation between the level and pattern of SOX9 expression in the liver and outcome of the liver disease in patients with ALGS.<\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n Our results establish Sox9<\/jats:italic> as a dosage\u2010sensitive modifier of Jag1+\/\u2212\n <\/jats:italic> liver phenotypes with a permissive role in biliary development. Our data further suggest that liver\u2010specific increase in SOX9 levels is a potential therapeutic approach for BD paucity in ALGS.<\/jats:p>\n <\/jats:sec>","DOI":"10.1002\/hep.30912","type":"journal-article","created":{"date-parts":[[2019,8,30]],"date-time":"2019-08-30T12:33:53Z","timestamp":1567168433000},"page":"1331-1349","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":33,"title":["Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome"],"prefix":"10.1097","volume":"71","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9556-9499","authenticated-orcid":false,"given":"Joshua M.","family":"Adams","sequence":"first","affiliation":[{"name":"Program in Developmental Biology,Baylor College of Medicine,Houston,TX"},{"name":"Medical Scientist Training Program,Baylor College of Medicine,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kari A.","family":"Huppert","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Cincinnati Children\u2019s Hospital Medical Center,Cincinnati,OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eumenia C.","family":"Castro","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology,Baylor College of Medicine,Houston,TX"},{"name":"Department of Pathology,Texas Children\u2019s Hospital,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mario F.","family":"Lopez","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nima","family":"Niknejad","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Cincinnati Children\u2019s Hospital Medical Center,Cincinnati,OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neda","family":"Zarrin\u2010Khameh","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology,Baylor College of Medicine,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Milton J.","family":"Finegold","sequence":"additional","affiliation":[{"name":"Department of Pathology & Immunology,Baylor College of Medicine,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacey S.","family":"Huppert","sequence":"additional","affiliation":[{"name":"Division of Gastroenterology, Hepatology and Nutrition,Cincinnati Children\u2019s Hospital Medical Center,Cincinnati,OH"},{"name":"Department of Pediatrics,University of Cincinnati College of Medicine,Cincinnati,OH"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hamed","family":"Jafar\u2010Nejad","sequence":"additional","affiliation":[{"name":"Program in Developmental Biology,Baylor College of Medicine,Houston,TX"},{"name":"Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"276","published-online":{"date-parts":[[2020,1,24]]},"reference":[{"key":"hep30912-bib-0001-20241017","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0070-2153(10)92001-2","article-title":"Notch: the past, the present, and the future","volume":"92","year":"2010","journal-title":"Curr Top Dev Biol"},{"key":"hep30912-bib-0002-20241017","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1016\/j.devcel.2017.04.001","article-title":"The canonical notch signaling pathway: structural and 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