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Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B.

Abstract : Netrins are secreted molecules with roles in axon guidance and angiogenesis. We identified Netrin-4 as a gene specifically overexpressed in VEGF-stimulated endothelial cells (EC) in vitro as well as in vivo. Knockdown of Netrin-4 expression in EC increased their ability to form tubular structures on Matrigel. To identify which receptor is involved, we showed by quantitative RT-PCR that EC express three of the six Netrin-1 cognate receptors: neogenin, Unc5B, and Unc5C. In contrast to Netrin-1, Netrin-4 bound only to neogenin but not to Unc5B or Unc5C receptors. Neutralization of Netrin-4 binding to neogenin by blocking antibodies abolished the chemotactic effect of Netrin-4. Furthermore, the silencing of either neogenin or Unc5B abolished Netrin-4 inhibitory effect on EC migration, suggesting that both receptors are essential for its function in vitro. Coimmunoprecipitation experiments demonstrated that Netrin-4 increased the association between Unc5B and neogenin on VEGF- or FGF-2-stimulated EC. Finally, we showed that Netrin-4 significantly reduced pathological angiogenesis in Matrigel and laser-induced choroidal neovascularization models. Interestingly, Netrin-4, neogenin, and Unc5B receptor expression was up-regulated in choroidal neovessel EC after laser injury. Moreover, Netrin-4 overexpression delayed tumor angiogenesis in a model of s.c. xenograft. We propose that Netrin-4 acts as an antiangiogenic factor through binding to neogenin and recruitment of Unc5B.
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Submitted on : Monday, September 1, 2008 - 7:17:56 PM
Last modification on : Tuesday, May 31, 2022 - 10:20:13 AM
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Esma Lejmi, Laurence Leconte, Sandrine Pédron-Mazoyer, Stanislas Ropert, William Raoul, et al.. Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B.. Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2008, 105 (34), pp.12491-6. ⟨10.1073/pnas.0804008105⟩. ⟨inserm-00315946⟩



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