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

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    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 Expression
    Document Type
    Journal Article
    Publication Date
    2013-04-01
    Keywords
    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
    Vegfc
    Angiogenesis
    Lymphatic
    Zebrafish
    Animal Experimentation and Research
    Cellular and Molecular Physiology
    Developmental Biology
    Embryonic Structures
    Genetic Phenomena
    Hemic and Immune Systems
    Investigative Techniques
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    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.
    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.084152
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/28842
    PubMed ID
    23462469
    Related Resources

    Link to Article in PubMed

    Rights
    Publisher PDF posted as allowed by the publisher's author rights policy at http://dev.biologists.org/site/misc/rights_permissions.xhtml#author
    ae974a485f413a2113503eed53cd6c53
    10.1242/dev.084152
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