A truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development
Authors
Villefranc, Jacques A.Nicoli, Stefania
Bentley, Katie
Jeltsch, Michael
Zarkada, Georgia
Moore, John C.
Gerhardt, Holger
Alitalo, Kari
Lawson, Nathan D.
UMass Chan Affiliations
Program in Gene Function and ExpressionDocument Type
Journal ArticlePublication Date
2013-04-01Keywords
AllelesAnimals
Animals, Genetically Modified
Autocrine Communication
Blood Vessels
Cell Movement
Codon, Nonsense
Embryo, Nonmammalian
Female
Lymphatic System
Mice
Mice, Knockout
Neovascularization, Physiologic
Paracrine Communication
Protein Isoforms
Signal Transduction
Vascular Endothelial Growth Factor C
Zebrafish
Zebrafish Proteins
Vegfc
Angiogenesis
Lymphatic
Zebrafish
Animal Experimentation and Research
Cellular and Molecular Physiology
Developmental Biology
Embryonic Structures
Genetic Phenomena
Hemic and Immune Systems
Investigative Techniques
Metadata
Show full item recordAbstract
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, vegfc(um18) 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.Source
Development. 2013 Apr;140(7):1497-506. doi: 10.1242/dev.084152. Epub 2013 Mar 5. Link to article on publisher's site
DOI
10.1242/dev.084152Permanent Link to this Item
http://hdl.handle.net/20.500.14038/28842PubMed ID
23462469Related Resources
Rights
Publisher PDF posted as allowed by the publisher's author rights policy at http://dev.biologists.org/site/misc/rights_permissions.xhtml#authorae974a485f413a2113503eed53cd6c53
10.1242/dev.084152