Suppression of Oct4 by Germ Cell Nuclear Factor Restricts Pluripotency and Promotes Neural Stem Cell Development in the Early Neural Lineage
Suppression of Oct4 by Germ Cell Nuclear Factor Restricts Pluripotency and Promotes Neural Stem Cell Development in the Early Neural Lineage
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DOI：
10.1523/jneurosci.4527-08.2009
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发表时间：
2009-02-18
影响因子：
5.3
通讯作者：
van der Kooy, Derek
中科院分区：
文献类型：
--
作者：
Akamatsu, Wado;DeVeale, Brian;van der Kooy, Derek
最早的鼠神经干细胞是白血病抑制因子（LIF）依赖的原始神经干细胞，其可以从胚胎干细胞或早期胚胎分离。这些原始神经干细胞具有分化为非神经组织的能力，并在体内胚胎第7.5天和第8.5天之间转变为FGF 2依赖性的永久性神经干细胞，伴随着非神经能力的降低。我们发现Oct 4在LIF依赖的原始神经干细胞中表达，在FGF依赖的永久神经干细胞中被抑制。在缺乏生殖细胞核因子（GCNF）的小鼠中，Oct 4的转录抑制因子，永久性神经干细胞的产生被显着抑制，伴随着Oct 4在早期神经外胚层的持续表达。GCNF（-/-）神经干细胞中Oct 4的敲低挽救了GCNF（-/-）表型。Oct 4的过度表达阻断了原始神经干细胞向定形神经干细胞的分化，但不诱导定形神经干细胞向原始神经干细胞的去分化。这些结果表明，原始神经干细胞通过GCNF诱导的Oct 4抑制发育为永久性神经干细胞。Oct 4启动子在从原始神经干细胞到定形神经干细胞的发育过程中被甲基化，而这些神经干细胞通过GCNF依赖的机制丧失其多能性。因此，GCNF对Oct 4的抑制对于从原始神经干细胞向定形神经干细胞的转变以及限制早期神经干细胞谱系中的非神经能力是重要的。
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.