Wnt/-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating notch activity

Publikation: Beitrag in FachzeitschriftForschungsartikelBeigetragenBegutachtung


  • Juhoon So - , University of Pittsburgh (Autor:in)
  • Mehwish Khaliq - , University of Pittsburgh (Autor:in)
  • Kimberley Evason - , University of Utah Hospital, University of California at Irvine (Autor:in)
  • Nikolay Ninov - , Professur für Zellbiologie und Regeneration von Betazellen, University of California at Irvine, Yale University, Max Planck Gesellschaft, Forschungsgruppe "Soziale Neurowissenschaften" (Autor:in)
  • Benjamin L. Martin - , Stony Brook University (Autor:in)
  • Didier Y. R. Stainier - , University of California at Irvine, Max Planck Gesellschaft, Forschungsgruppe "Soziale Neurowissenschaften" (Autor:in)
  • Donghun Shin - , University of Pittsburgh (Autor:in)


Malformations of the intrahepatic biliary structure cause cholestasis, a liver pathology that corresponds to poor bile flow, which leads to inflammation, fibrosis, and cirrhosis. Although the specification of biliary epithelial cells (BECs) that line the bile ducts is fairly well understood, the molecular mechanisms underlying intrahepatic biliary morphogenesis remain largely unknown. Wnt/-catenin signaling plays multiple roles in liver biology; however, its role in intrahepatic biliary morphogenesis remains unclear. Using pharmacological and genetic tools that allow one to manipulate Wnt/-catenin signaling, we show that in zebrafish both suppression and overactivation of Wnt/-catenin signaling impaired intrahepatic biliary morphogenesis. Hepatocytes, but not BECs, exhibited Wnt/-catenin activity; and the global suppression of Wnt/-catenin signaling reduced Notch activity in BECs. Hepatocyte-specific suppression of Wnt/-catenin signaling also reduced Notch activity in BECs, indicating a cell nonautonomous role for Wnt/-catenin signaling in regulating hepatic Notch activity. Reducing Notch activity to the same level as that observed in Wnt-suppressed livers also impaired biliary morphogenesis. Intriguingly, expression of the Notch ligand genes jag1b and jag2b in hepatocytes was reduced in Wnt-suppressed livers and enhanced in Wnt-overactivated livers, revealing their regulation by Wnt/-catenin signaling. Importantly, restoring Notch activity rescued the biliary defects observed in Wnt-suppressed livers. Conclusion: Wnt/-catenin signaling cell nonautonomously controls Notch activity in BECs by regulating the expression of Notch ligand genes in hepatocytes, thereby regulating biliary morphogenesis. (Hepatology 2018;67:2352-2366).


Seiten (von - bis)2352-2366
PublikationsstatusVeröffentlicht - Juni 2018

Externe IDs

PubMed 29266316
Scopus 85047848787



  • Bile-duct development, Liver development, Beta-catenin, Alagille-syndrome, Mice, Differentiation, Jagged1, Growth, Fate, Tubulogenesis