Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis (original) (raw)

  1. Romain H. Fontaine1,2,3,18,
  2. Jihane Soueid1,2,3,18,
  3. Tuomas Tammela4,5,
  4. Taija Makinen4,5,
  5. Clara Alfaro-Cervello6,
  6. Fabien Bonnaud7,
  7. Andres Miguez1,2,3,
  8. Lucile Benhaim1,2,3,
  9. Yunling Xu8,
  10. Maria-José Barallobre9,
  11. Imane Moutkine1,2,3,
  12. Johannes Lyytikkä10,
  13. Turgut Tatlisumak10,
  14. Bronislaw Pytowski11,
  15. Bernard Zalc1,2,3,12,
  16. William Richardson13,14,
  17. Nicoletta Kessaris13,14,
  18. Jose Manuel Garcia-Verdugo6,15,
  19. Kari Alitalo4,5,
  20. Anne Eichmann8,16 and
  21. Jean-Léon Thomas1,2,3,12,17,19
  22. 1University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, UMR S975, Paris 75651, France;
  23. 2Inserm, U975, Paris 75651, France;
  24. 3CNRS, UMR 7225, Paris 75651, France;
  25. 4Molecular/Cancer Biology Laboratory, Biomedicum Helsinki, University of Helsinki, Helsinki FI-00290, Finland;
  26. 5Department of Pathology, Haartman Institute, University of Helsinki, Helsinki FI-00290, Finland;
  27. 6Laboratorio de Morfología Celular, Centro de Investigación Príncipe Felipe, CIBERNED, Valencia 46013, Spain;
  28. 7Cellular Imaging and Analysis, PerkinElmer, Coventry HP9 2FX, United Kingdom;
  29. 8Center for Interdisciplinary Research in Biology (CIRB), Collège de France, Paris 75005, France;
  30. 9Center for Genomic Regulation, UPF and CIBER de Enfermedades Raras, Barcelona 08003, Spain;
  31. 10Experimental MRI Laboratory, Department of Neurology, Helsinki University Central Hospital, Helsinki FI-00290, Finland;
  32. 11ImClone Systems, New York, New York 10016, USA;
  33. 12Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris 75651, France;
  34. 13Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, United Kingdom;
  35. 14Research Department of Cell and Developmental Biology, University College London, London WC1E 6BT, United Kingdom;
  36. 15Laboratorio de Neurobiología Comparada, Instituto Cavanilles, Universidad de Valencia, Valencia 46980, Spain;
  37. 16Department of Cardiology, Yale University School of Medicine, Connecticut 06511, USA;
  38. 17Department of Neurology, Yale University School of Medicine, Connecticut 06511, USA
  39. ↵18 These authors contributed equally to this work.

Abstract

Neural stem cells (NSCs) are slowly dividing astrocytes that are intimately associated with capillary endothelial cells in the subventricular zone (SVZ) of the brain. Functionally, members of the vascular endothelial growth factor (VEGF) family can stimulate neurogenesis as well as angiogenesis, but it has been unclear whether they act directly via VEGF receptors (VEGFRs) expressed by neural cells, or indirectly via the release of growth factors from angiogenic capillaries. Here, we show that VEGFR-3, a receptor required for lymphangiogenesis, is expressed by NSCs and is directly required for neurogenesis. Vegfr3:YFP reporter mice show VEGFR-3 expression in multipotent NSCs, which are capable of self-renewal and are activated by the VEGFR-3 ligand VEGF-C in vitro. Overexpression of VEGF-C stimulates VEGFR-3-expressing NSCs and neurogenesis in the SVZ without affecting angiogenesis. Conversely, conditional deletion of Vegfr3 in neural cells, inducible deletion in subventricular astrocytes, and blocking of VEGFR-3 signaling with antibodies reduce SVZ neurogenesis. Therefore, VEGF-C/VEGFR-3 signaling acts directly on NSCs and regulates adult neurogenesis, opening potential approaches for treatment of neurodegenerative diseases.

Footnotes