1月16日,《分子細胞生物學雜誌》(Journal of Molecular Cell Biology)在線發表了中科院上海生科院生化與細胞所朱學良研究組的研究論文:「Nanog suppresses cell migration by downregulating Thymosin β4 and Rnd3」。該研究發現幹細胞轉錄因子Nanog可通過下調下遊基因Thymosin β4和Rnd3的表達來抑制細胞的遷移,提示Nanog等轉錄因子能夠在調控胚胎幹細胞乾性的同時影響細胞的遷移能力。
細胞遷移對胚胎發育的組織、器官形成等有重要貢獻。幹細胞需要在一些特定的轉錄因子的作用下才能維持其乾性,在細胞分化的過程中這些轉錄因子的表達會被抑制。細胞分化往往也會伴隨細胞遷移能力的變化。但這種變化是因為維持乾性的轉錄因子也參與調節細胞遷移,還是僅僅因為分化後細胞的性質發生了根本改變?
朱學良研究組的研究生周釔灼等發現,在普通培養細胞內異位表達Nanog、Oct4、Sox2等幹細胞轉錄因子能夠顯著抑制細胞的遷移。針對Nanog的進一步研究發現它通過下調Thymosin β4 and Rnd3兩個蛋白來影響微絲骨架的排布和粘著斑的定位,進而抑制細胞的遷移。Thymosin β4和Rnd3在小鼠的胚胎幹細胞分化過程中的表達量與Nanog負相關,而在具有多分化潛能的小鼠畸胎瘤P19細胞內敲低Nanog的表達則能夠促進細胞遷移。由於已知Nanog的表達水平在斑馬魚的囊胚階段高,但在原腸運動後期急劇下降,在體實驗選取斑馬魚早期胚胎作為研究對象,發現在斑馬魚胚胎中持續性表達Nanog會抑制原腸運動過程中的細胞遷移。這些研究結果提示Nanog等轉錄因子具有調節乾性和遷移能力的雙重作用,這種兩面性可能有助於細胞分化和遷移的協調。
該課題得到了國家科技部、國家自然科學基金委和中國科學院的資助。(生物谷Bioon.com)
Nanog suppresses cell migration by downregulating thymosin β4 and Rnd3.
Zhou Y, Li S, Huang Q, Xie L, Zhu X.
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