02701nas a2200469 4500008004100000022001400041245014300055210006900198260001300267300001300280490000800293520127600301653001201577653001201589653003401601653002801635653001801663653001801681653002001699653002501719653001101744653002101755653000901776653001901785653003601804653002801840653002101868653002401889653004101913653001401954653002301968100002701991700002102018700001902039700002102058700002102079700001902100700002102119700001802140700002202158856005102180 2013 eng d a1477-912900aA truncation allele in vascular endothelial growth factor c reveals distinct modes of signaling during lymphatic and vascular development.0 atruncation allele in vascular endothelial growth factor c reveal c2013 Apr a1497-5060 v1403 a
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.
10aAlleles10aAnimals10aAnimals, Genetically Modified10aAutocrine Communication10aBlood Vessels10aCell Movement10aCodon, Nonsense10aEmbryo, Nonmammalian10aFemale10aLymphatic System10aMice10aMice, Knockout10aNeovascularization, Physiologic10aParacrine Communication10aProtein Isoforms10aSignal Transduction10aVascular Endothelial Growth Factor C10aZebrafish10aZebrafish Proteins1 aVillefranc, Jacques, A1 aNicoli, Stefania1 aBentley, Katie1 aJeltsch, Michael1 aZarkada, Georgia1 aMoore, John, C1 aGerhardt, Holger1 aAlitalo, Kari1 aLawson, Nathan, D uhttps://jeltsch.org/Villefranc2013?language=en