Netrin-4 acts as a pro-angiogenic factor during zebrafish development
- Authors
- Lambert, E., Coissieux, M.M., Laudet, V., and Mehlen, P.
- ID
- ZDB-PUB-120105-64
- Date
- 2012
- Source
- The Journal of biological chemistry 287(6): 3987-3999 (Journal)
- Registered Authors
- Laudet, Vincent
- Keywords
- angiogenesis, apoptosis, axon, MAP kinases (MAPKs), zebrafish, netrin
- MeSH Terms
-
- Cells, Cultured
- Endothelial Cells/cytology
- Endothelial Cells/metabolism*
- Neovascularization, Physiologic/drug effects
- Neovascularization, Physiologic/physiology*
- Nerve Growth Factors/genetics
- Nerve Growth Factors/metabolism*
- Animals
- Zebrafish/embryology*
- Zebrafish/genetics
- Zebrafish Proteins/genetics
- Zebrafish Proteins/metabolism*
- Angiogenesis Inducing Agents/metabolism*
- Protein Kinases/genetics
- Protein Kinases/metabolism
- Animals, Genetically Modified/embryology
- Animals, Genetically Modified/genetics
- Morpholinos/pharmacology
- Humans
- Enzyme Activation/drug effects
- Enzyme Activation/physiology
- PubMed
- 22179604 Full text @ J. Biol. Chem.
Netrins form an heterogeneous family of laminin related molecules with multifunctional activities. Netrin-4, the most distant member of this family, is related to the laminin beta 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 (HUVECs and HUAECs) and 2 zebrafish models: the wild-type AB/Tu 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 evidence that Netrin-4 activates various kinases and induces various biological effects directly linked to angiogenesis in vitro. Using morpholinos strategy, we demonstrate that Netrin-4 expression is crucial for zebrafish vessel formation and that blood vessel formation defect induced by netrin-4 morpholinos can be partially rescued through drug delivery leading to protein kinase activation. Together these data underline 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.