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Suppression of Oct4 by Germ Cell Nuclear Factor Restricts Pluripotency and Promotes Neural Stem Cell Development in the Early Neural Lineage
Open accessAbstract
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.
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NR6A1 is a nuclear receptor with a role in neurogenesis.
“Two of them (L152 and F456) are in a region necessary for the interaction with NR6A140, a nuclear receptor with a role in neurogenesis41.”
From Distinct selective forces and Neanderthal introgression shaped genetic diversity at genes involved in neurodevelopmental disorders (2017) · cites this paper as [41]
The Introduction calls GCNF an orphan nuclear receptor, and the Discussion describes its role in the transition from primitive to definitive neural stem cells. Our copy does not identify GCNF as NR6A1, so it cannot establish that the named receptor has that role. (LLM, conf=0.72)
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References 30 · Cited by 72
Research works printed but not linked: 1
- Seaberg, 2002, The identification and chimeric characterization of primitive and definitive mammalian neural stem cells, Soc Neurosci Abstr, 28, 726
Metadata
- Authors
- Akamatsu, W., DeVeale, B., Okano, H., Cooney, A. J., & van der Kooy, D.
- Affiliations
- University of Toronto (CA)
- Keio University (JP)
- Baylor College of Medicine (US)
- Venue
- The Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2009-02-18
- Volume
- 29
- Issue
- 7
- Pages
- 2113-2124
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6666351
- OpenAlex
- W2043018786
- Cited by
- 72
- References
- 30
- Citations by year
- 2026: 1 · 2025: 1 · 2023: 3 · 2022: 3 · 2021: 2 · 2020: 2 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 7 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 2.51
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Canadian Institutes of Health Research
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- Oct4, GCNF, neural stem cell differentiation, pluripotency, DNA methylation, Oct4 promoter, neuroectoderm, transcriptional repression, dedifferentiation
- MeSH terms
- Animals, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Ectoderm, Mice, Inbred C57BL, Nervous System, Down-Regulation, Receptors, Cytoplasmic and Nuclear, Mice, Knockout, Gene Expression Regulation, Developmental, Cell Lineage, Pluripotent Stem Cells, Octamer Transcription Factor-3, Mice, Neural Tube, Neurogenesis, Nuclear Receptor Subfamily 6, Group A, Member 1
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