PUBLICATION

Hepatocyte Growth Factor Signaling in Intrapancreatic Ductal Cells Drives Pancreatic Morphogenesis

Authors
Anderson, R.M., Delous, M., Bosch, J.A., Ye, L., Robertson, M.A., Hesselson, D., and Stainier, D.Y.
ID
ZDB-PUB-130729-3
Date
2013
Source
PLoS Genetics   9(7): e1003650 (Journal)
Registered Authors
Anderson, Ryan, Stainier, Didier
Keywords
Pancreas, Embryos, Tails, Zebrafish, Larvae, Cell membranes, Phenotypes, Morphogenesis
MeSH Terms
  • Signal Transduction*
  • Phosphatidylinositol 3-Kinases/antagonists & inhibitors
  • Phosphatidylinositol 3-Kinases/metabolism
  • STAT3 Transcription Factor/antagonists & inhibitors
  • STAT3 Transcription Factor/metabolism
  • Animals
  • Pancreatic Ducts/growth & development*
  • Pancreatic Ducts/metabolism
  • Hepatocyte Growth Factor/metabolism*
  • Proto-Oncogene Proteins c-met/genetics*
  • Proto-Oncogene Proteins c-met/metabolism
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Mutation, Missense
  • Morphogenesis*
  • Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases/metabolism
(all 17)
PubMed
23935514 Full text @ PLoS Genet.
Abstract

In a forward genetic screen for regulators of pancreas development in zebrafish, we identified donuts908, a mutant which exhibits failed outgrowth of the exocrine pancreas. The s908 mutation leads to a leucine to arginine substitution in the ectodomain of the hepatocyte growth factor (HGF) tyrosine kinase receptor, Met. This missense mutation impedes the proteolytic maturation of the receptor, its trafficking to the plasma membrane, and diminishes the phospho-activation of its kinase domain. Interestingly, during pancreatogenesis, met and its hgf ligands are expressed in pancreatic epithelia and mesenchyme, respectively. Although Met signaling elicits mitogenic and migratory responses in varied contexts, normal proliferation rates in donut mutant pancreata together with dysmorphic, mislocalized ductal cells suggest that met primarily functions motogenically in pancreatic tail formation. Treatment with PI3K and STAT3 inhibitors, but not with MAPK inhibitors, phenocopies the donut pancreatic defect, further indicating that Met signals through migratory pathways during pancreas development. Chimera analyses showed that Met-deficient cells were excluded from the duct, but not acinar, compartment in the pancreatic tail. Conversely, wild-type intrapancreatic duct and “tip cells” at the leading edge of the growing pancreas rescued the donut phenotype. Altogether, these results reveal a novel and essential role for HGF signaling in the intrapancreatic ducts during exocrine morphogenesis.

Genes / Markers
Figures
Figure Gallery (8 images)
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Expression
Phenotype
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
gz15TgTransgenic Insertion
    ia3TgTransgenic Insertion
      jh1TgTransgenic Insertion
        m1018TgTransgenic Insertion
          s892TgTransgenic Insertion
            s908
              Point Mutation
              s961TgTransgenic Insertion
                1 - 7 of 7
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                Human Disease / Model
                No data available
                Sequence Targeting Reagents
                Target Reagent Reagent Type
                hgfaMO1-hgfaMRPHLNO
                hgfbMO1-hgfbMRPHLNO
                metMO1-metMRPHLNO
                1 - 3 of 3
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                Fish
                Antibodies
                Name Type Antigen Genes Isotypes Host Organism
                Ab3-prox1polyclonalRabbit
                zn-5monoclonalIgG1Mouse
                1 - 2 of 2
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                Orthology
                No data available
                Engineered Foreign Genes
                Marker Marker Type Name
                CFPEFGCFP
                DsRedEFGDsRed
                EGFPEFGEGFP
                emGFPEFGemGFP
                GFPEFGGFP
                mCherryEFGmCherry
                NTREFGNTR
                1 - 7 of 7
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                Mapping
                No data available