5E). HNF-6 loss may thus contribute to the ductular response in the setting of cholestatic liver injury seen in DKO mice. However, this explanation by itself would not account for the restoration of HNF-1β expression. An alternate pathway or effector may thus drive the ductular proliferative response, and may or may not do so through improved expression of HNF-1β. Candidates include separate pathways such as Wnt or Hedgehog signaling.26, 27 Still, Dabrafenib the observed abnormalities in both IHBD cast structure and CK-positive BECs indicate a severe defect in the formation of the communicating intrahepatic biliary system with loss

of both HNF-6 and Notch signaling. There was a worsening of cholestatic liver disease associated with severe abnormalities in IHBD development in DKO mice. This was evidenced by an increase in total bilirubin and alkaline phosphatase

compared to RBP-J loss alone (Table 1), as well as extensive hepatic necrosis and bridging fibrosis (Fig. 2D). To date, HNF-6 polymorphisms have not been described in patients Selleckchem Kinase Inhibitor Library with AGS. However, given that loss of HNF-6 in the setting of Notch signaling loss causes a clear phenotypic worsening of cholestatic liver disease, HNF-6 or downstream effectors may contribute to the clinical variability in disease phenotype that can be seen in patients with AGS.6, 28 In summary, our data indicate that HNF-6 find more and Notch signaling interact to affect expression of similar downstream mediators that are important in normal intrahepatic biliary development. We suggest that this interaction occurs along a parallel course, and loss of both HNF-6 and Notch signaling

leads to subsequent loss of HNF-1β and Sox9 expression. This continued requirement for HNF-6 in the postnatal expression of genetic effectors essential to IHBD development has not been described previously. The complex regulatory profile of HNF-1β and Sox9 presented in this study does not prove that alterations in expression of these molecules are responsible for the abnormalities in IHBD development in DKO mice. However, alterations in their expression during periods of continued BEC specification and morphogenesis suggest that the observed worsened BEC paucity in DKO mice compared to RBP-J loss alone may be related to genetic loss of these important factors. The cholestatic liver injury observed in the adult mouse occurs with an associated ductular response. We hypothesize this may represent the involvement of a yet undefined alternate signaling mechanism that leads to the appearance of a proliferative CK-positive cell population and improvement in HNF-1β expression.