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RESEARCH COMMUNICATION

Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling

¹ Department of Neurology, University of Tokyo, Tokyo 113-8655, Japan; ² Department of Medical Genetics and Microbiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada

Basic fibroblast growth factor (FGF2)-responsive definitive neural stem cells first appear in embryonic day 8.5 (E8.5) mouse embryos, but not in earlier embryos, although neural tissue exists at E7.5. Here, we demonstrate that leukemia inhibitory factor-dependent (but not FGF2-dependent) sphere-forming cells are present in the earlier (E5.5–E7.5) mouse embryo. The resultant clonal sphere cells possess self-renewal capacity and neural multipotentiality, cardinal features of the neural stem cell. However, they also retain some nonneural properties, suggesting that they are the in vivo cells' equivalent of the primitive neural stem cells that form in vitro from embryonic stem cells. The generation of the in vivo primitive neural stem cell was independent of Notch signaling, but the activation of the Notch pathway was important for the transition from the primitive to full definitive neural stem cell properties and for the maintenance of the definitive neural stem cell state.

[Keywords: Neural stem cell; embryonic stem cell; epiblast; neuroectoderm; leukemia inhibitory factor; Notch signaling]

Received March 31, 2004; revised version accepted May 26, 2004.

³ Present address: Division of Neurobiology & Bioinformatics, National Institute for Physiological Sciences, Aichi 444-8585, Japan.

Corresponding authors.

⁴ E-MAIL shitoshi{at}nips.ac.jp; FAX 81-564-59-5247.

⁵ E-MAIL derek.van.der.kooy{at}utoronto.ca; FAX (416) 978-3844.

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