University of Massachusetts Medical School Faculty Publications

UMMS Affiliation

Program in Gene Function and Expression

Publication Date

2013-04-01

Document Type

Article

Subjects

Alleles; Animals; 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

Disciplines

Animal Experimentation and Research | Cellular and Molecular Physiology | Developmental Biology | Embryonic Structures | Genetic Phenomena | Hemic and Immune Systems | Investigative Techniques

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, 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.

Keywords

Vegfc, Angiogenesis, Lymphatic, Zebrafish

Rights and Permissions

Publisher PDF posted as allowed by the publisher's author rights policy at http://dev.biologists.org/site/misc/rights_permissions.xhtml#author

DOI of Published Version

10.1242/dev.084152

Source

Development. 2013 Apr;140(7):1497-506. doi: 10.1242/dev.084152. Epub 2013 Mar 5. Link to article on publisher's site

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Development (Cambridge, England)

PubMed ID

23462469

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