title: Vascular endothelial growth factor receptor 3 directly regulates murine neurogenesis.
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.
authors.affiliation: University Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epiniere, UMR S975, Paris 75651, France.
authors.forename: Charles-Félix
authors.initials: CF
authors.lastname: Calvo
authors.forename: Romain H
authors.initials: RH
authors.lastname: Fontaine
authors.forename: Jihane
authors.initials: J
authors.lastname: Soueid
authors.forename: Tuomas
authors.initials: T
authors.lastname: Tammela
authors.forename: Taija
authors.initials: T
authors.lastname: Makinen
authors.forename: Clara
authors.initials: C
authors.lastname: Alfaro-Cervello
authors.forename: Fabien
authors.initials: F
authors.lastname: Bonnaud
authors.forename: Andres
authors.initials: A
authors.lastname: Miguez
authors.forename: Lucile
authors.initials: L
authors.lastname: Benhaim
authors.forename: Yunling
authors.initials: Y
authors.lastname: Xu
authors.forename: Maria-José
authors.initials: MJ
authors.lastname: Barallobre
authors.forename: Imane
authors.initials: I
authors.lastname: Moutkine
authors.forename: Johannes
authors.initials: J
authors.lastname: Lyytikkä
authors.forename: Turgut
authors.initials: T
authors.lastname: Tatlisumak
authors.forename: Bronislaw
authors.initials: B
authors.lastname: Pytowski
authors.forename: Bernard
authors.initials: B
authors.lastname: Zalc
authors.forename: William
authors.initials: W
authors.lastname: Richardson
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Kessaris
authors.forename: Jose Manuel
authors.initials: JM
authors.lastname: Garcia-Verdugo
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.forename: Anne
authors.initials: A
authors.lastname: Eichmann
authors.forename: Jean-Léon
authors.initials: JL
authors.lastname: Thomas
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D042583:Lymphangiogenesis / Q000235:genetics / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D040321:Vascular Endothelial Growth Factor Receptor-3