PUBLICATION

Core Hippo pathway components act as a brake on Yap/Taz in the development and maintenance of the biliary network

Authors
Brandt, Z.J., Echert, A.E., Bostrom, J.R., North, P.N., Link, B.A.
ID
ZDB-PUB-200524-5
Date
2020
Source
Development (Cambridge, England)   147(12): (Journal)
Registered Authors
Link, Brian
Keywords
Cholangiocarcinoma, Gallbladder, Hepatopancreatic ductal system, Hippo pathway, Sav1, Stk3
MeSH Terms
  • Signal Transduction
  • Larva/growth & development
  • Larva/metabolism
  • Carboxylic Ester Hydrolases/metabolism
  • Animals
  • Liver/anatomy & histology
  • Liver/metabolism
  • CRISPR-Cas Systems/genetics
  • Phenotype
  • Transcription Factors/genetics
  • Transcription Factors/metabolism*
  • Biliary Tract/anatomy & histology
  • Biliary Tract/growth & development
  • Biliary Tract/metabolism*
  • Zebrafish/growth & development
  • Zebrafish/metabolism
  • Protein Serine-Threonine Kinases/deficiency
  • Protein Serine-Threonine Kinases/genetics
  • Protein Serine-Threonine Kinases/metabolism*
  • Zebrafish Proteins/deficiency
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
  • Gallbladder/anatomy & histology
  • Gallbladder/growth & development
  • Gallbladder/metabolism
  • Animals, Genetically Modified/growth & development
  • Animals, Genetically Modified/metabolism
  • Trans-Activators/genetics
  • Trans-Activators/metabolism*
(all 29)
PubMed
32439761 Full text @ Development
Abstract
The development of the biliary system is a complex yet poorly understood process, with relevance to multiple diseases including biliary atresia, choledochal cysts, and gallbladder agenesis. We present here a crucial role for Hippo-Yap/Taz signaling in this context. Analysis of sav1 mutant zebrafish revealed dysplastic morphology and expansion of both intrahepatic and extrahepatic biliary cells, and ultimately larval lethality. Biliary dysgenesis, but not larval lethality, is driven primarily by Yap signaling. Re-expression of Sav1 protein in sav1-/- hepatocytes is able to overcome these initial deficits and allow sav1-/- fish to survive, suggesting cell non-autonomous signaling from hepatocytes. Examination of sav1-/- rescued adults reveals loss of gallbladder and formation of dysplastic cell masses expressing biliary markers suggesting roles for Hippo signaling in extrahepatic biliary carcinomas. Deletion of stk3 revealed the phenotypes observed in sav1 mutant fish function primarily through canonical Hippo signaling and supports a role for phosphatase PP2A, but also suggests Sav1 has functions in addition to facilitating Stk3 activity. Overall, this study defines a role for Hippo-Yap signaling in the maintenance of both intra- and extrahepatic biliary ducts.
Genes / Markers
Figures
Figure Gallery (11 images) / 2
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Expression
Phenotype
Fish Conditions Stage Phenotype Figure
sav1mw95/mw95standard conditionsProtruding-mouth
sav1mw95/mw95standard conditionsDay 5
sav1mw95/mw95standard conditionsDay 5
sav1mw95/mw95standard conditionsDay 5
sav1mw95/mw95standard conditionsDay 5
sav1mw95/mw95standard conditionsDay 6
sav1mw95/mw95standard conditionsDay 6
sav1mw95/mw95standard conditionsDay 6
sav1mw95/mw95standard conditionsDays 7-13
sav1mw95/mw95standard conditionsDays 7-13
1 - 10 of 57
Show
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
mw48
    		Small Deletion
    mw49
      		Small Deletion
      mw75TgTransgenic Insertion
        mw95
          		Insertion
          mw96
            		Small Deletion
            mw97TgTransgenic Insertion
              1 - 6 of 6
              Show
              Human Disease / Model
              No data available
              Sequence Targeting Reagents
              Target Reagent Reagent Type
              sav1CRISPR1-sav1CRISPR
              stk3TALEN1-stk3TALEN
              1 - 2 of 2
              Show
              Fish
              Fish
              mw75Tg
              mw97Tg
              sav1mw95/mw95
              sav1mw95/mw95; mw75Tg
              sav1mw95/mw95; mw97Tg
              stk3mw96/mw96
              stk3mw96/mw96; sav1mw95/mw95
              stk3mw96/mw96; yap1mw48/mw48
              WT
              wwtr1mw49/mw49
              1 - 10 of 13
              Show
              Antibodies
              Orthology
              No data available
              Engineered Foreign Genes
              Marker Marker Type Name
              EGFPEFGEGFP
              GFPEFGGFP
              1 - 2 of 2
              Show
              Mapping
              No data available
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              Citation
              Brandt, Z.J., Echert, A.E., Bostrom, J.R., North, P.N., Link, B.A. (2020) Core Hippo pathway components act as a brake on Yap/Taz in the development and maintenance of the biliary network. Development (Cambridge, England). 147(12):.