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

Esma Lejmi 1 Laurence Leconte 1, * Sandrine Pédron-Mazoyer 1 Stanislas Ropert 1 William Raoul 2 Sophie Lavalette 2 Ilyes Bouras 1 Jean-Guillaume Feron 1 Martine Maitre-Boube 1 Franck Assayag 3 Charles Feumi 2 Monica Alemany 1 Tan Xian Jie 1 Tatyana Merkulova 1 Marie-France Poupon 3, 4 Marie-Magdeleine Ruchoux 1 Gérard Tobelem 1 Florian Sennlaub 2 Jean Plouët 1
* Corresponding author
1 Centre de Recherche Cardiovasculaire de Lariboisiere
2 CRC (UMR_S 872) - Centre de Recherche des Cordeliers
3 DIGBFC - Dynamique de l'information génétique : bases fondamentales et cancer
4 Laboratoire de Recherche Translationnelle
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
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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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