PUBLICATION

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

Authors
So, J., Khaliq, M., Evason, K., Ninov, N., Martin, B.L., Stainier, D.Y.R., Shin, D.
ID
ZDB-PUB-171222-11
Date
2017
Source
Hepatology (Baltimore, Md.)   67(6): 2352-2366 (Journal)
Registered Authors
Evason, Kimberley, Khaliq, Mehwish, Martin, Benjamin, Ninov, Nikolay, Shin, Donghun, So, Juhoon, Stainier, Didier
Keywords
Notch signaling, bile canaliculi, biliary epithelial cells, biliary morphogenesis, liver development
MeSH Terms
  • Animals
  • Bile Ducts, Intrahepatic/growth & development*
  • Morphogenesis*
  • Receptors, Notch/physiology*
  • Wnt Signaling Pathway/physiology*
  • Zebrafish
(all 6)
PubMed
29266316 Full text @ Hepatology
Abstract
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/β-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/β-catenin signaling, we show here that in zebrafish, both the suppression and overactivation of Wnt/β-catenin signaling impaired intrahepatic biliary morphogenesis. Hepatocytes, but not BECs, exhibited Wnt/β-catenin activity, and the global suppression of Wnt/β-catenin signaling reduced Notch activity in BECs. Hepatocyte-specific suppression of Wnt/β-catenin signaling also reduced Notch activity in BECs, indicating a cell non-autonomous role for Wnt/β-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, the 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/β-catenin signaling. Importantly, restoring Notch activity rescued the biliary defects observed in Wnt-suppressed livers.
Conclusion Wnt/β-catenin signaling cell non-autonomously controls Notch activity in BECs by regulating the expression of Notch ligand genes in hepatocytes, thereby regulating biliary morphogenesis. This article is protected by copyright. All rights reserved.
Genes / Markers
Marker Marker Type Name
axin2GENEaxin 2 (conductin, axil)
bcl2aGENEBCL2 apoptosis regulator a
eef1a1l1GENEeukaryotic translation elongation factor 1 alpha 1, like 1
fzd10GENEfrizzled class receptor 10
fzd2GENEfrizzled class receptor 2
fzd4GENEfrizzled class receptor 4
fzd5GENEfrizzled class receptor 5
fzd8aGENEfrizzled class receptor 8a
fzd9aGENEfrizzled class receptor 9a
her15.1GENEhairy and enhancer of split-related 15, tandem duplicate 1
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Figures
No images available
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
WTchemical treatment by environment: LY-411575Day 5
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
WTchemical treatment by environment: XAV939Day 4
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
co17TgTransgenic Insertion
    gd2GtTransgenic Insertion
    kyu1TgTransgenic Insertion
      nkhg21cEtTransgenic Insertion
      pt603TgTransgenic Insertion
        pt611TgTransgenic Insertion
          pt612TgTransgenic Insertion
            s704TgTransgenic Insertion
              s939TgTransgenic Insertion
                s940TgTransgenic Insertion
                  1 - 10 of 15
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                  Human Disease / Model
                  No data available
                  Sequence Targeting Reagents
                  No data available
                  Fish
                  Fish
                  co17Tg; s939Tg
                  co17Tg; s939Tg; s940Tg
                  co17Tg; um14Tg
                  kyu1Tg; pt611Tg
                  pt612Tg
                  pt612Tg; s704Tg
                  s704Tg
                  s704Tg; s733Tg
                  s704Tg; um14Tg
                  s733Tg
                  1 - 10 of 17
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                  Antibodies
                  Orthology
                  Engineered Foreign Genes
                  Marker Marker Type Name
                  d2EGFPEFGd2EGFP
                  ECFPEFGECFP
                  EGFPEFGEGFP
                  GFPEFGGFP
                  mCherryEFGmCherry
                  TFPEFGTFP
                  VenusEFGVenus
                  YFPEFGYFP
                  1 - 8 of 8
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                  Mapping
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                  Citation
                  So, J., Khaliq, M., Evason, K., Ninov, N., Martin, B.L., Stainier, D.Y.R., Shin, D. (2017) Wnt/β-catenin signaling controls intrahepatic biliary network formation in zebrafish by regulating Notch activity. Hepatology (Baltimore, Md.). 67(6):2352-2366.