生物通报道：来自中科院上海生命科学研究院生物化学与细胞生物学研究所的朱学良研究组发表了题为“Nanog suppresses cell migration by downregulating Thymosin β4 and Rnd3”的文章，发现干细胞转录因子Nanog可通过下调下游基因Thymosin β4和Rnd3的表达来抑制细胞的迁移，从而指出了Nanog等转录因子具有调节干性和迁移能力的双重作用，而这种两面性可能有助于细胞分化和迁移的协调。相关成果公布在Journal of Molecular Cell Biology杂志上。

细胞迁移对胚胎发育的组织、器官形成等有重要贡献。干细胞需要在一些特定的转录因子的作用下才能维持其干性，在细胞分化的过程中这些转录因子的表达会被抑制。细胞分化往往也会伴随细胞迁移能力的变化。但这种变化是因为维持干性的转录因子也参与调节细胞迁移，还是仅仅因为分化后细胞的性质发生了根本改变？

在这篇文章中，研究人员发现在普通培养细胞内异位表达Nanog、Oct4、Sox2等干细胞转录因子能够显著抑制细胞的迁移。针对Nanog的进一步研究发现它通过下调Thymosin β4 and Rnd3两个蛋白来影响微丝骨架的排布和粘着斑的定位，进而抑制细胞的迁移。Thymosin β4和Rnd3在小鼠的胚胎干细胞分化过程中的表达量与Nanog负相关，而在具有多分化潜能的小鼠畸胎瘤P19细胞内敲低Nanog的表达则能够促进细胞迁移。

由于已知Nanog的表达水平在斑马鱼的囊胚阶段高，但在原肠运动后期急剧下降，在体实验选取斑马鱼早期胚胎作为研究对象，发现在斑马鱼胚胎中持续性表达Nanog会抑制原肠运动过程中的细胞迁移。这些研究结果提示Nanog等转录因子具有调节干性和迁移能力的双重作用，这种两面性可能有助于细胞分化和迁移的协调。

此前这一研究组还提出了Nudel作为动力蛋白调节因子的新功能，并描述了这一蛋白通过结合Sra1 和HSPC300亚基，在WAVE复合物的体内组装过程中发挥了重要作用。

研究指出，Nudel能够稳定WAVE复合物中Sra1、Nap1和Abi1形成的异源三聚体和HSPC300形成的同源三聚体，并促进HSPC300同WAVE2的结合。利用RNA干扰技术抑制Nudel的表达可以引起WAVE复合物及其亚基的蛋白质水平下调，WAVE复合物依赖性的微丝聚合也相应地受到抑制，说明Nudel的这些作用有助于WAVE复合物的体内组装。

研究人员据此提出了WAVE复合物在细胞内组装过程的模型图。这些研究结果为Nudel在细胞迁移中的功能提供了新的知识。

原文摘要：

Nanog suppresses cell migration by downregulating Thymosin β4 and Rnd3

Nanog, Sox2, and Oct4 are key transcription factors critical for the pluripotency and self-renewal of embryonic stem 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 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 embryonic stem 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.

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