State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
J Mol Cell Biol. 2013 Aug;5(4):239-49. doi: 10.1093/jmcb/mjt002. Epub 2013 Jan 16.
Nanog, Sox2, and Oct4 are key transcription factors critical for the pluripotency and self-renewal of embryonic stem (ES) cells. Their downregulations lead to differentiation, accompanied with changes in cell motility. Whether these factors impact cell motility directly, however, is not clear. Here we addressed this question by initially assessing their effect in non-stem cells. We found that the ectopic expression of Nanog, Sox2, or Oct4 markedly inhibited ECV304 cell migration. Detailed examinations revealed that Nanog induced disorganizations of the actin cytoskeleton and peripheral localizations of focal adhesions. These effects required its DNA-binding domain and are thus transcription dependent. Furthermore, thymosin β4 and Rnd3 were identified as its downstream targets. Their depletions in ECV304 cells by RNAi phenocopied the ectopic expression of Nanog in both cell motility and actin organization, whereas their ectopic expressions rescued the migration defect of Nanog overexpression. Both proteins were upregulated during mouse ES cell differentiation. Their levels in the pluripotent mouse P19 cells also increased upon Nanog ablation, coincident with an increase in cell motility. Moreover, persistent expression of Nanog in zebrafish embryos suppressed gastrulation and cell migration. These results indeed suggest a dual role of certain transcription factors in the orchestration of differentiation and motility.
Nanog、Sox2 和 Oct4 是胚胎干细胞（ES 细胞）多能性和自我更新的关键转录因子。它们的下调会导致分化，并伴随着细胞迁移能力的变化。然而，这些因子是否直接影响细胞迁移能力尚不清楚。在这里，我们通过最初评估它们在非干细胞中的作用来解决这个问题。我们发现 Nanog、Sox2 或 Oct4 的异位表达显著抑制了 ECV304 细胞的迁移。详细检查显示，Nanog 诱导肌动蛋白细胞骨架的紊乱和焦点粘连的外周定位。这些效应需要其 DNA 结合域，因此是转录依赖性的。此外，胸腺素 β4 和 Rnd3 被鉴定为其下游靶标。在 ECV304 细胞中通过 RNAi 耗尽它们，在细胞迁移和肌动蛋白组织方面表现出 Nanog 的异位表达，而它们的异位表达则挽救了 Nanog 过表达的迁移缺陷。这两种蛋白质在小鼠 ES 细胞分化过程中均上调。在 Nanog 缺失后，多能性小鼠 P19 细胞中的它们的水平也增加，同时细胞迁移能力也增加。此外，斑马鱼胚胎中持续表达 Nanog 抑制了原肠胚形成和细胞迁移。这些结果确实表明某些转录因子在分化和运动的协调中具有双重作用。
