Netrins were described as bifunctional guidance cues, capable of attracting or repelling developing axons via activation of receptors of the deleted in colorectal cancer (DCC) and uncoordinated 5 (UNC5) families, respectively. Recently, they have also been implicated in the process of blood-vessel formation or angiogenesis, where they may also act as bifunctional cues, but their effect is unclear, with previous reports showing contradictory endothelial behaviors. In order to clarify the pro- or anti-angiogenic role of the signaling pathway initiated by netrins on endothelial cells, combined in vitro and in vivo approaches will be pursued. We will be focused on the cellular situation previous to the stimulation of different types of endothelial cells. Homogenous populations on arterial, venous and microvascular endothelial cells will be analyzed. We will carry out a compared screening of mRNA levels on resting, proliferating or differentiating endothelial cells, on situations of netrin1 or 4 stimulation and baseline. Expression pattern of candidate molecules differentially regulated will be further characterized in developing zebrafish and mice by in situ hybridization. To rule out the active role of those molecules during developmental angiogenesis, the candidate will study their role on zebrafish development by both loss- and gain-of function approaches, using new powerful genetic tools. These genetic studies will be complemented with in vitro assays to document the navigation of endothelial tip cells and how gene up- down-regulation can affect the tip/stalk behavior, to dissect the pro- or anti-angiogenic signaling pathways induced by netrin1 and 4.
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