title: Netrin-4 acts as a pro-angiogenic factor during zebrafish development.
abstract: Netrins form a heterogeneous family of laminin-related molecules with multifunctional activities. Netrin-4, the most distant member of this family, is related to the laminin β chain and has recently been proposed to play an important role in embryonic and pathological angiogenesis. However, the data reported so far lead to the apparently contradictory conclusions supporting Netrin-4 as either a pro- or an anti-angiogenic factor. To elucidate this controversy, Netrin-4 was analyzed for a vascular activity in both cell-based models (human umbilical vein endothelial cells and human umbilical artery endothelial cells) and two zebrafish models: the wild-type AB/Tü strain and the transgenic Tg(fli1a:EGFP)(y1) strain. We show that Netrin-4 is expressed in endothelial cells and in the zebrafish vascular system. We also show evidence that Netrin-4 activates various kinases and induces various biological effects directly linked to angiogenesis in vitro. Using a morpholinos strategy, we demonstrate that Netrin-4 expression is crucial for zebrafish vessel formation and that a blood vessel formation defect induced by netrin-4 morpholinos can be partially rescued through drug delivery leading to protein kinase activation. Together these data underscore the crucial role of Netrin-4 in blood vessel formation and the involvement of protein kinases activation in Netrin-4-induced biological effects related to vascular development.
authors.affiliation: Apoptosis, Cancer, and Development Laboratory, Equipe labellisée La Ligue, LabEx DEVweCAN, Centre de Cancérologie de Lyon, INSERM U1052, CNRS UMR5286, Université de Lyon, 28 rue Laënnec, Lyon 69008, France.
authors.forename: Elise
authors.initials: E
authors.lastname: Lambert
authors.forename: Marie-May
authors.initials: MM
authors.lastname: Coissieux
authors.forename: Vincent
authors.initials: V
authors.lastname: Laudet
authors.forename: Patrick
authors.initials: P
authors.lastname: Mehlen
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified / Q000196:embryology / Q000235:genetics; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D060172:Morpholinos / Q000494:pharmacology; D018919:Neovascularization, Physiologic / Q000187:drug effects / Q000502:physiology*; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D000075385:Netrins; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D043925:Angiogenesis Inducing Agents; D060172:Morpholinos; D009414:Nerve Growth Factors; D000075385:Netrins; D029961:Zebrafish Proteins; C506551:ntn4 protein, zebrafish; D011494:Protein Kinases