title: Vascular endothelial growth factor directly inhibits primitive neural stem cell survival but promotes definitive neural stem cell survival.
abstract: There are two types of neural stem cells (NSCs). Primitive NSCs [leukemia inhibitory factor (LIF) dependent but exogenous fibroblast growth factor (FGF) 2 independent] can be derived from mouse embryonic stem (ES) cells in vitro and from embryonic day 5.5 (E5.5) to E7.5 epiblast and E7.5-E8.5 neuroectoderm in vivo. Definitive NSCs (LIF independent but FGF2 dependent) first appear in the E8.5 neural plate and persist throughout life. Primitive NSCs give rise to definitive NSCs. Loss and gain of functions were used to study the role of vascular endothelial growth factor (VEGF)-A and its receptor, Flk1, in NSCs. The numbers of Flk1 knock-out mice embryo-derived and ES cell-derived primitive NSCs were increased because of the enhanced survival of primitive NSCs. In contrast, neural precursor-specific, Flk1 conditional knock-out mice-derived, definitive NSCs numbers were decreased because of the enhanced cell death of definitive NSCs. These effects were not observed in cells lacking Flt1, another VEGF receptor. In addition, the cell death stimulated by VEGF-A of primitive NSC and the cell survival stimulated by VEGF-A of definitive NSC were blocked by Flk1/Fc-soluble receptors and VEGF-A function-blocking antibodies. These VEGF-A phenotypes also were blocked by inhibition of the downstream effector nuclear factor kappaB (NF-kappaB). Thus, both the cell death of primitive NSC and the cell survival of definitive NSC induced by VEGF-A stimulation are mediated by bifunctional NF-kappaB effects. In conclusion, VEGF-A function through Flk1 mediates survival (and not proliferative or fate change) effects on NSCs, specifically.
authors.affiliation: Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada M5S 3E1. tamaki.wada@utoronto.ca
authors.forename: Tamaki
authors.initials: T
authors.lastname: Wada
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
authors.forename: Masatsugu
authors.initials: M
authors.lastname: Ema
authors.forename: Seiji
authors.initials: S
authors.lastname: Hitoshi
authors.forename: Radha
authors.initials: R
authors.lastname: Chaddah
authors.forename: Janet
authors.initials: J
authors.lastname: Rossant
authors.forename: Andras
authors.initials: A
authors.lastname: Nagy
authors.forename: Derek
authors.initials: D
authors.lastname: van der Kooy
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002934:Cinnamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005326:Fetal Proteins / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D020287:In Situ Nick-End Labeling / Q000379:methods; D019394:Ki-67 Antigen / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013234:Stem Cells / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D020825:T-Box Domain Proteins / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000172:deficiency; D000098908:Brachyury Protein
chemical_list: D002934:Cinnamates; D004791:Enzyme Inhibitors; D005326:Fetal Proteins; D019394:Ki-67 Antigen; D012333:RNA, Messenger; D020825:T-Box Domain Proteins; D042461:Vascular Endothelial Growth Factor A; D040301:Vascular Endothelial Growth Factor Receptor-2; D000098908:Brachyury Protein; C483044:SU 1498