Sox9 Is a Modifier of the Liver Disease Severity in a Mouse Model of Alagille Syndrome

• DOI: 10.1002/hep.30912
• Publication Date: 2019-08-30T12:33:53Z
• Authors: Joshua M. Adams; Kari A. Huppert; Eumenia C. Castro; Mario F. Lopez; Nima Niknejad; Sanjay Subramanian; Neda Zarrin‐Khameh; Milton J. Finegold; Stacey S. Huppert; Hamed Jafar‐Nejad
• Keywords: JAG1; Alagille Syndrome; Haploinsufficiency; SOX9; Liver disease

Background and Aims Alagille syndrome (ALGS) is a multisystem developmental disorder characterized by bile duct (BD) paucity, caused primarily haploinsufficiency of the Notch ligand jagged1. The course liver disease highly variable in ALGS. However, genetic basis for ALGS phenotypic variability unknown. Previous studies have reported decreased expression transcription factor SOX9 (sex determining region Y‐box 9) late embryonic neonatal livers Jag1 ‐deficient mice. Here, we investigated effects altering Sox9 gene dosage on severity an mouse model. Approach Results Conditional removal one copy Jag1+/− impairs biliary commitment cholangiocytes enhances inflammatory reaction fibrosis. Loss both copies further worsens phenotypes results partial lethality. Ink injection experiments reveal impaired tree formation periphery P30 livers, which improved 5 months age. heterozygosity phenotype recovery 5‐month‐old animals. Notably, overexpression improves BD paucity mice without ectopic hepatocyte‐to‐cholangiocyte transdifferentiation or long‐term abnormalities. Notch2 increased following overexpression, binds regulatory liver. Histological analysis shows correlation between level pattern outcome patients with Conclusions Our establish as dosage‐sensitive modifier permissive role development. data suggest that liver‐specific increase levels potential therapeutic approach