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The Journal of Neuroscience, February 18, 2009, 29(7):2113-2124; doi:10.1523/JNEUROSCI.4527-08.2009

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Development/Plasticity/Repair
Suppression of Oct4 by Germ Cell Nuclear Factor Restricts Pluripotency and Promotes Neural Stem Cell Development in the Early Neural Lineage

Wado Akamatsu,^1,2 Brian DeVeale,¹ Hideyuki Okano,² Austin J Cooney,³ and Derek van der Kooy¹

¹Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada M5S3E1, ²Department of Physiology, Keio University School of Medicine, Tokyo 160-8582, Japan, and ³Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Correspondence should be addressed to either of the following: Wado Akamatsu or Derek van der Kooy, Department of Molecular Genetics, University of Toronto, 160 College Street Room 1102, Toronto, Ontario, Canada M5S3E1. Email: wado{at}sc.itc.keio.ac.jp; or Email: derek.van.der.kooy{at}utoronto.ca

The earliest murine neural stem cells are leukemia inhibitory factor (LIF)-dependent, primitive neural stem cells, which can be isolated from embryonic stem cells or early embryos. These primitive neural stem cells have the ability to differentiate to non-neural tissues and transition into FGF2-dependent, definitive neural stem cells between embryonic day 7.5 and 8.5 in vivo, accompanied by a decrease in non-neural competency. We found that Oct4 is expressed in LIF-dependent primitive neural stem cells and suppressed in FGF-dependent definitive neural stem cells. In mice lacking germ cell nuclear factor (GCNF), a transcriptional repressor of Oct4, generation of definitive neural stem cells was dramatically suppressed, accompanied by a sustained expression of Oct4 in the early neuroectoderm. Knockdown of Oct4 in GCNF^–/– neural stem cells rescued the GCNF^–/– phenotype. Overexpession of Oct4 blocked the differentiation of primitive to definitive neural stem cells, but did not induce the dedifferentiation of definitive to primitive neural stem cells. These results suggested that primitive neural stem cells develop into definitive neural stem cells by means of GCNF induced suppression of Oct4. The Oct4 promoter was methylated during the development from primitive neural stem cell to definitive neural stem cell, while these neural stem cells lose their pluripotency through a GCNF dependent mechanism. Thus, the suppression of Oct4 by GCNF is important for the transition from primitive to definitive neural stem cells and restriction of the non-neural competency in the early neural stem cell lineage.

Key words: stem cells; development; ectoderm; differentiation; growth factor; neural precursor

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Received Sept. 22, 2008; revised Jan. 6, 2009; accepted Jan. 8, 2009.

Correspondence should be addressed to either of the following: Wado Akamatsu or Derek van der Kooy, Department of Molecular Genetics, University of Toronto, 160 College Street Room 1102, Toronto, Ontario, Canada M5S3E1. Email: wado{at}sc.itc.keio.ac.jp; or Email: derek.van.der.kooy{at}utoronto.ca

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