ZFIN ID: ZDB-PUB-141009-4
carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) regulates Notch signaling and vascular development in zebrafish
Coxam, B., Neyt, C., Grassini, D.R., Le Guen, L., Smith, K.A., Schulte-Merker, S., Hogan, B.M.
Date: 2015
Source: Developmental dynamics : an official publication of the American Association of Anatomists   244(1): 1-9 (Journal)
Registered Authors: Coxam, Baptiste, Hogan, Ben M., Le Guen, Ludovic, Neyt, Christine, Schulte-Merker, Stefan, Smith, Kelly
Keywords: Notch, Vegfc, angiogenesis, glycosylation, lymphangiogenesis, zebrafish
MeSH Terms:
  • Animals
  • Aspartate Carbamoyltransferase/genetics
  • Aspartate Carbamoyltransferase/metabolism*
  • Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/genetics
  • Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing)/metabolism*
  • Dihydroorotase/genetics
  • Dihydroorotase/metabolism*
  • Glycosylation
  • Neovascularization, Physiologic/physiology*
  • Receptors, Notch/genetics
  • Receptors, Notch/metabolism*
  • Signal Transduction/physiology*
  • Vascular Endothelial Growth Factor C/genetics
  • Vascular Endothelial Growth Factor C/metabolism
  • Vascular Endothelial Growth Factor Receptor-3/genetics
  • Vascular Endothelial Growth Factor Receptor-3/metabolism
  • Zebrafish/embryology*
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism
PubMed: 25294789 Full text @ Dev. Dyn.
Background: The interplay between Notch and Vegf signaling regulates angiogenesis in the embryo. Notch signaling limits the responsiveness of endothelial cells to Vegf to control sprouting. Despite the importance of this regulatory relationship, much remains to be understood about extrinsic factors that modulate the pathway. Results: During a forward genetic screen for novel regulators of lymphangiogenesis, we isolated a mutant with reduced lymphatic vessel development. This mutant also exhibited hyperbranching arteries, reminiscent of Notch pathway mutants. Positional cloning identified a missense mutation in the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (cad) gene. Cad is essential for UDP biosynthesis, which is necessary for protein glycosylation and de novo biosynthesis of pyrimidine-based nucleotides. Using a transgenic reporter of Notch activity, we demonstrate that Notch signaling is significantly reduced in cad(hu10125) mutants. In this context, genetic epistasis showed that increased endothelial cell responsiveness to Vegfc/Vegfr3 signaling drives excessive artery branching. Conclusion: These findings suggest important post-translational modifications requiring Cad as an unappreciated mechanism that regulates Notch/Vegf signaling during angiogenesis.