title: Jagged1 heterozygosity in mice results in a congenital cholangiopathy which is reversed by concomitant deletion of one copy of Poglut1 (Rumi).
abstract: Haploinsufficiency for the Notch ligand JAG1 in humans results in an autosomal-dominant, multisystem disorder known as Alagille syndrome, which is characterized by a congenital cholangiopathy of variable severity. Here, we show that on a C57BL/6 background, jagged1 heterozygous mice (Jag1(+/-) ) exhibit impaired intrahepatic bile duct (IHBD) development, decreased SOX9 expression, and thinning of the periportal vascular smooth muscle cell (VSMC) layer, which are apparent at embryonic day 18 and the first postnatal week. In contrast, mice double heterozygous for Jag1 and the glycosyltransferase, Poglut1 (Rumi), start showing a significant improvement in IHBD development and VSMC differentiation during the first week. At P30, Jag1(+/-) mice show widespread ductular reactions and ductopenia in liver and a mild, but statistically, significant bilirubinemia. In contrast, P30 Jag1/Rumi double-heterozygous mice show well-developed portal triads around most portal veins, with no elevation of serum bilirubin. Conditional deletion of Rumi in VSMCs results in progressive arborization of the IHBD tree, whereas deletion of Rumi in hepatoblasts frequently results in an increase in the number of hepatic arteries without affecting bile duct formation. Nevertheless, removing one copy of Rumi from either VSMCs or hepatoblasts is sufficient to partially suppress the Jag1(+/-) bile duct defects. Finally, all Rumi target sites of the human JAG1 are efficiently glucosylated, and loss of Rumi in VSMCs results in increased levels of full-length JAG1 and a shorter fragment of JAG1 without affecting Jag1 messenger RNA levels.
  
  
  CONCLUSIONS
  On a C57BL/6 background, Jag1 haploinsufficiency results in bile duct paucity in mice. Removing one copy of Rumi suppresses the Jag1(+/-) bile duct phenotype, indicating that Rumi opposes JAG1 function in the liver.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Shakeel M
authors.initials: SM
authors.lastname: Thakurdas
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.
authors.forename: Mario F
authors.initials: MF
authors.lastname: Lopez
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY.
authors.forename: Shinako
authors.initials: S
authors.lastname: Kakuda
authors.affiliation: Department of Pathology, School of Medicine, Wayne State University, Detroit, MI.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Fernandez-Valdivia
authors.affiliation: Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX.
authors.forename: Neda
authors.initials: N
authors.lastname: Zarrin-Khameh
authors.affiliation: Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY.
authors.forename: Robert S
authors.initials: RS
authors.lastname: Haltiwanger
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX.|Program in Developmental Biology, Baylor College of Medicine, Houston, TX.
authors.forename: Hamed
authors.initials: H
authors.lastname: Jafar-Nejad
mesh_terms: D000818:Animals; D001649:Bile Duct Diseases / Q000151:congenital* / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D017353:Gene Deletion; D005964:Glucosyltransferases / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D000072100:Jagged-1 Protein; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D000072099:Serrate-Jagged Proteins
chemical_list: D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D000072099:Serrate-Jagged Proteins; D005964:Glucosyltransferases; C510651:POGLUT1 protein, human