Protein fucosylation is required for Notch dependent vascular integrity in zebrafish

Fowler, G., French, D., Rose, A., Squires, P., Anecito da Silva, C., Ohata, S., Okamoto, H., French, C.R.
Developmental Biology   480: 62-68 (Journal)
Registered Authors
French, Curtis R., Ohata, Shinya, Okamoto, Hitoshi
Endothelial cell, Fucosylation, Hemorrhage, Mural cell, Notch signaling, Zebrafish, gmds
MeSH Terms
  • Animals
  • Body Patterning/genetics
  • Cell Differentiation/genetics
  • Cell Movement/genetics
  • Endothelial Cells/metabolism*
  • Fucose/metabolism
  • Glycosylation
  • Guanosine Diphosphate Fucose/metabolism
  • Hemorrhage/genetics
  • Hemorrhage/prevention & control
  • Hydro-Lyases/genetics
  • Hydro-Lyases/metabolism*
  • Loss of Function Mutation/genetics
  • Mutation
  • Phenotype
  • Receptors, Notch/metabolism*
  • Receptors, Notch/physiology
  • Signal Transduction
  • Zebrafish/metabolism
  • Zebrafish Proteins/metabolism
34400136 Full text @ Dev. Biol.
The onset of circulation in a developing embryo requires intact blood vessels to prevent hemorrhage. The development of endothelial cells, and their subsequent recruitment of perivascular mural cells are important processes to establish and maintain vascular integrity. These processes are genetically controlled during development, and mutations that affect endothelial cell specification, pattern formation, or maturation through the addition of mural cells can result in early developmental hemorrhage. We created a strong loss of function allele of the zebrafish GDP-mannose 4,6 dehydratase (gmds) gene that is required for the de novo synthesis of GDP-fucose, and homozygous embryos display cerebral hemorrhages. Our data demonstrate that gmds mutants have early defects in vascular patterning with ectopic branches observed at time of hemorrhage. Subsequently, defects in the number of mural cells that line the vasculature are observed. Moreover, activation of Notch signaling rescued hemorrhage phenotypes in gmds mutants, highlighting a potential downstream pathway that requires protein fucosylation for vascular integrity. Finally, supplementation with fucose can rescue hemorrhage frequency in gmds mutants, demonstrating that synthesis of GDP-fucose via this alternative (salvage) pathway may provide an avenue toward therapeutic correction of phenotypes observed due to defects in the de novo GDP-fucose synthesis. Together, these data are consistent with a novel role for the de novo and salvage protein fucosylation pathways in regulating vascular integrity through a Notch dependent mechanism.
Genes / Markers
Show all Figures
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Engineered Foreign Genes