title: Vascular endothelial growth factor receptor 3 controls neural stem cell activation in mice and humans.
abstract: Neural stem cells (NSCs) continuously produce new neurons within the adult mammalian hippocampus. NSCs are typically quiescent but activated to self-renew or differentiate into neural progenitor cells. The molecular mechanisms of NSC activation remain poorly understood. Here, we show that adult hippocampal NSCs express vascular endothelial growth factor receptor (VEGFR) 3 and its ligand VEGF-C, which activates quiescent NSCs to enter the cell cycle and generate progenitor cells. Hippocampal NSC activation and neurogenesis are impaired by conditional deletion of Vegfr3 in NSCs. Functionally, this is associated with compromised NSC activation in response to VEGF-C and physical activity. In NSCs derived from human embryonic stem cells (hESCs), VEGF-C/VEGFR3 mediates intracellular activation of AKT and ERK pathways that control cell fate and proliferation. These findings identify VEGF-C/VEGFR3 signaling as a specific regulator of NSC activation and neurogenesis in mammals.
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Jinah
authors.initials: J
authors.lastname: Han
authors.affiliation: Université Pierre and Marie Curie-Paris 6, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; INSERM/CNRS U-1127/UMR-7225, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France.
authors.forename: Charles-Félix
authors.initials: CF
authors.lastname: Calvo
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Tae Hyuk
authors.initials: TH
authors.lastname: Kang
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Kasey L
authors.initials: KL
authors.lastname: Baker
authors.affiliation: Department of Neurology, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: June-Hee
authors.initials: JH
authors.lastname: Park
authors.affiliation: Université Pierre and Marie Curie-Paris 6, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; INSERM/CNRS U-1127/UMR-7225, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France.
authors.forename: Carlos
authors.initials: C
authors.lastname: Parras
authors.affiliation: Université Pierre and Marie Curie-Paris 6, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; INSERM/CNRS U-1127/UMR-7225, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Levittas
authors.affiliation: Université Pierre and Marie Curie-Paris 6, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; INSERM/CNRS U-1127/UMR-7225, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France.
authors.forename: Ulrick
authors.initials: U
authors.lastname: Birba
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Pibouin-Fragner
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Pascal
authors.initials: P
authors.lastname: Fragner
authors.affiliation: Department of Genetics, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Kaya
authors.initials: K
authors.lastname: Bilguvar
authors.affiliation: Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06510-3221, USA.
authors.forename: Ronald S
authors.initials: RS
authors.lastname: Duman
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Harri
authors.initials: H
authors.lastname: Nurmi
authors.affiliation: Wihuri Research Institute and Translational Cancer Biology Program, Biomedicum Helsinki, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Kari
authors.initials: K
authors.lastname: Alitalo
authors.affiliation: Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06510-3221, USA. Electronic address: anne.eichmann@yale.edu.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Eichmann
authors.affiliation: Université Pierre and Marie Curie-Paris 6, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; INSERM/CNRS U-1127/UMR-7225, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; APHP, Groupe Hospitalier Pitié-Salpètrière, 75013 Paris, France; Department of Neurology, Yale University School of Medicine, New Haven, CT 06510-3221, USA. Electronic address: jean-leon.thomas@yale.edu.
authors.forename: Jean-Léon
authors.initials: JL
authors.lastname: Thomas
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D002478:Cells, Cultured; D053595:Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055495:Neurogenesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000494:pharmacology; D015398:Signal Transduction; D042582:Vascular Endothelial Growth Factor C / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D011994:Recombinant Proteins; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases