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
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Morphogenesis*
  • Animals
  • Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors
  • Mitogen-Activated Protein Kinase Kinases/metabolism
  • Signal Transduction*
  • Pancreatic Ducts/growth & development*
  • Pancreatic Ducts/metabolism
  • Mutation, Missense
  • Hepatocyte Growth Factor/metabolism*
  • STAT3 Transcription Factor/antagonists & inhibitors
  • STAT3 Transcription Factor/metabolism
  • Phosphatidylinositol 3-Kinases/antagonists & inhibitors
  • Phosphatidylinositol 3-Kinases/metabolism
  • Proto-Oncogene Proteins c-met/genetics*
  • Proto-Oncogene Proteins c-met/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
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
Orthology
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