5 and postnatal day 7. These time points allowed them to examine hilar IHBD formation of the ductal plate, PDS, and mature duct. All three of the mouse models in this study highlight defects at different steps of bile duct tubulogenesis. The absence of HNF6 caused a somewhat resolvable early defect in biliary cell differentiation, whereas liver-specific loss of HNF1β produced a defect in PDS maturation. A third type of defect is observed in the absence of cystin-1, where an abnormal expansion of ducts was observed even though the biliary cells differentiate normally. All three specific biliary tubulogenesis defects result in an endpoint

of DPM. Specifically, examination of differentiation in Hnf6−/− mice revealed that cells lining lumens did not express the cholangiocyte marker SOX9, but did express the hepatocyte marker HNF4 at embryonic day 17.5. These data are in agreement with earlier studies that established deficient

selleckchem HNF6 generates hybrid hepatobiliary cells and indicates that HNF6 is required for differentiation of biliary cells at embryonic stages.9 Postnatally, the biliary differentiation was resolved, supported by the presence of SOX9+/HNF4− selleck products cholangiocytes. However, normal tubulogenesis did not proceed and resulted in DPM observed in hilar IHBDs at postnatal day 7. A different result was observed for Hnf1bloxP/loxPAlfp-Cre mice. Absence of HNF1β resulted in normal embryonic SOX9+/HNF4− expression around the forming bile duct lumen on the portal side, but the parenchymal side of the bile duct lumen remained SOX9−/HNF4+ throughout the liver. This is inconsistent with the progressive nature of bile duct tubulogenesis, asserting that the bile duct structures at the hilar region should be more mature than the ductal structures at the peripheral regions. The subsequent postnatal see more phenotype displayed differentiation of SOX9+/HNF4− cholangiocytes, but with observed DPM and dysplastic ducts. This phenotype was consistent with the patient samples analyzed that carried HNF1B (TCF2; Mendelian Inheritance in Man #137920) mutations. These results support an early

differentiation role of HNF6 and a PDS maturation role for HNF1β, providing two different defects in tubulogenesis prior to the endpoint of DPM. Deficient cystin-1 (cpk−/−) does not lead to defects in differentiation at any stage of biliary tubulogenesis, but does cause DPM as also observed in human patients with ARPKD. These data demonstrate that deficient maturation during tubulogenesis is a cause of DPM. Cholangiocyte polarity was also disrupted at varying degrees of severity in each of the three mouse models. The apical-basal polarity in cases of deficient HNF6 and HNF1β was strongly affected. Apical expression of osteopontin was absent, in addition to abnormal localization of centrioles and Golgi apparatus.