title: Development of the zebrafish lymphatic system requires VEGFC signaling.
abstract: Lymphangiogenesis results in the formation of a vascular network distinct from arteries and veins that serves to drain interstitial fluid from surrounding tissues and plays a pivotal role in the immune defense of vertebrates as well as in the progression of cancer and other diseases . In mammals, lymph vessels are lined by endothelial cells possibly sprouting from embryonic veins, and their development appears to be critically dependent on the function of PROX1 and VEGFC signaling . The existence of a lymphatic system in teleosts has been a matter of debate for decades. Here we show on the morphological, molecular, and functional levels that zebrafish embryos develop a lymphatic vasculature that serves to retrieve components of the interstitium to the lymph system. We demonstrate the existence of vessels that are molecularly and functionally distinct from blood vessels and show that the development of these vessels depends on Vegfc and VEGFR-3/Flt4 signaling. These findings imply that the molecular components controlling lymphangiogenesis in zebrafish and mammals are conserved and that the zebrafish lymphatic system develops early enough to allow in vivo observations, lineage tracing, and genetic as well as pharmacological screens.
authors.affiliation: Exelixis, Inc., 170 Harbor Way, South San Francisco, California 94083, USA.
authors.forename: Axel M
authors.initials: AM
authors.lastname: Küchler
authors.forename: Evisa
authors.initials: E
authors.lastname: Gjini
authors.forename: Josi
authors.initials: J
authors.lastname: Peterson-Maduro
authors.forename: Belinda
authors.initials: B
authors.lastname: Cancilla
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.forename: Stefan
authors.initials: S
authors.lastname: Schulte-Merker
mesh_terms: D042702:Angiopoietin-2 / Q000378:metabolism; D000818:Animals; D030801:Animals, Genetically Modified / Q000033:anatomy & histology / Q000378:metabolism; D001692:Biological Transport; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D004729:Endothelium, Lymphatic / Q000166:cytology / Q000378:metabolism; D045604:Extracellular Fluid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000032:analysis; D042601:Lymphatic Vessels / Q000196:embryology* / Q000378:metabolism; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism*; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: D042702:Angiopoietin-2; D042582:Vascular Endothelial Growth Factor C; D029961:Zebrafish Proteins; C493178:vascular endothelial growth factor C, zebrafish; D049452:Green Fluorescent Proteins; D040321:Vascular Endothelial Growth Factor Receptor-3