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The Journal of Neuroscience, June 21, 2006, 26(25):6803-6812; doi:10.1523/JNEUROSCI.0526-06.2006

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Development/Plasticity/Repair
Vascular Endothelial Growth Factor Directly Inhibits Primitive Neural Stem Cell Survival But Promotes Definitive Neural Stem Cell Survival

Tamaki Wada,¹ Jody J. Haigh,² Masatsugu Ema,² Seiji Hitoshi,¹ Radha Chaddah,¹ Janet Rossant,² Andras Nagy,² and Derek van der Kooy¹

¹Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario, Canada M5S 3E1, and ²Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5

Correspondence should be addressed to either Tamaki Wada or Derek van der Kooy, Department of Medical Genetics and Microbiology, University of Toronto, #1102 Donnelly CCBR, 160 College Street, Toronto, Ontario, Canada M5S 3E1. Email: tamaki.wada{at}utoronto.ca or derek.van.der.kooy{at}utoronto.ca

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 B (NF-B). 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-B effects. In conclusion, VEGF-A function through Flk1 mediates survival (and not proliferative or fate change) effects on NSCs, specifically.

Key words: neural stem cell; embryonic stem cell; VEGF-A; cell survival/death; neurosphere; NF-B

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Received Sept. 30, 2005; revised May 1, 2006; accepted May 2, 2006.

Correspondence should be addressed to either Tamaki Wada or Derek van der Kooy, Department of Medical Genetics and Microbiology, University of Toronto, #1102 Donnelly CCBR, 160 College Street, Toronto, Ontario, Canada M5S 3E1. Email: tamaki.wada{at}utoronto.ca or derek.van.der.kooy{at}utoronto.ca

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