Missexpression of Human JAGGED1 Causes Disorganization of The Biliary Tree in Zebrafish Consistent With a Biliary Atresia Phenotype

Abstract

Biliary atresia (BA) is a progressive, fibro-obliterative cholangiopathy of infants, which if left untreated is fatal. The pathogenesis of BA is not fully understood but may involve dysregulation of hepatic progenitor/stem cells (HPSC) during development of the biliary tree. Recent data indicate that ductular proliferation, a pathologic hallmark of BA, represents massive expansion of HPSC marked with an epithelial stem cell marker GCTM5 (Stamp et al, Stem Cells 2012). Alagille syndrome (AGS), a congenital disorder marked by a paucity of bile ducts, is caused by haploinsufficiency of JAGGED1 (JAG1), a gene that encodes a Notch pathway ligand critical for HPSC proliferation and differentiation at the onset of biliary organogenesis. Kohsaka et al reported that missense mutations in JAG1 occur in a subset of cases of BA and are associated with poorer prognosis (Hepatology 2004). Preliminary in vitro data indicate that these BA-associated JAG1 mutations result in increased Notch activity in contrast to AGS possibly through enhanced subcellular trafficking of ligand. We, therefore, hypothesized that in vivo misexpression of wild-type human JAG1 in transgenic zebrafish would result in increased Notch pathway activation, thus, disrupting biliary organogenesis leading to a disorganized biliary tree.