PUBLICATION

A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development

Authors
Villefranc, J.A., Nicoli, S., Bentley, K., Jeltsch, M., Zarkada, G., Moore, J.C., Gerhardt, H., Alitalo, K., and Lawson, N.D.
ID
ZDB-PUB-130322-28
Date
2013
Source
Development (Cambridge, England)   140(7): 1497-1506 (Journal)
Registered Authors
Lawson, Nathan, Moore, John, Nicoli, Stefania, Villefranc, Jacque
Keywords
Vegfc, angiogenesis, lymphatic, zebrafish
MeSH Terms
  • Alleles
  • Animals
  • Animals, Genetically Modified
  • Autocrine Communication/genetics
  • Autocrine Communication/physiology
  • Blood Vessels/embryology*
  • Blood Vessels/growth & development
  • Cell Movement/genetics
  • Cell Movement/physiology
  • Codon, Nonsense/physiology
  • Embryo, Nonmammalian
  • Female
  • Lymphatic System/embryology*
  • Lymphatic System/growth & development
  • Mice
  • Mice, Knockout
  • Neovascularization, Physiologic/genetics
  • Neovascularization, Physiologic/physiology
  • Paracrine Communication/genetics
  • Paracrine Communication/physiology
  • Protein Isoforms/genetics
  • Protein Isoforms/physiology
  • Signal Transduction/genetics
  • Vascular Endothelial Growth Factor C/genetics*
  • Vascular Endothelial Growth Factor C/physiology*
  • Zebrafish/embryology
  • Zebrafish/genetics
  • Zebrafish Proteins/genetics*
  • Zebrafish Proteins/physiology*
PubMed
23462469 Full text @ Development
Abstract

Vascular endothelial growth factor C (Vegfc) is a secreted protein that guides lymphatic development in vertebrate embryos. However, its role during developmental angiogenesis is not well characterized. Here, we identify a mutation in zebrafish vegfc that severely affects lymphatic development and leads to angiogenesis defects on sensitized genetic backgrounds. The um18 mutation prematurely truncated Vegfc, blocking its secretion and paracrine activity but not its ability to activate its receptor Flt4. When expressed in endothelial cells, vegfcum18 could not rescue lymphatic defects in mutant embryos, but induced ectopic blood vessel branching. Furthermore, vegfc-deficient endothelial cells did not efficiently contribute to tip cell positions in developing sprouts. Computational modeling together with assessment of endothelial cell dynamics by time-lapse analysis suggested that an autocrine Vegfc/Flt4 loop plays an important role in migratory persistence and filopodia stability during sprouting. Our results suggest that Vegfc acts in two distinct modes during development: as a paracrine factor secreted from arteries to guide closely associated lymphatic vasculature and as an autocrine factor to drive migratory persistence during angiogenesis.

Genes / Markers
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Expression
Phenotype
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping
Errata and Notes