Olig2-induced neural stem cell differentiation involves downregulation of Wnt signaling and induction of Dickkopf-1 expression.
Olig2-induced neural stem cell differentiation involves downregulation of Wnt signaling and induction of Dickkopf-1 expression.
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DOI：
10.1371/journal.pone.0003917
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发表时间：
2008
期刊：
影响因子：
3.7
通讯作者：
Lee B
中科院分区：
文献类型：
--
作者：
Ahn SM;Byun K;Kim D;Lee K;Yoo JS;Kim SU;Jho EH;Simpson RJ;Lee B
在分子水平上理解干细胞分化对于干细胞的临床应用和在癌症干细胞的背景下寻找新的治疗方法是重要的。为了研究参与分化的全基因组变化，我们使用永生化神经干细胞（NSC）系（HB 1.F3）和Olig 2诱导的NSC分化模型（F3.Olig2）。利用微阵列分析，我们发现Olig 2诱导的NSC分化涉及Wnt通路的下调，这进一步证实了TOPflash/FOPflash报告基因分析，RT-PCR分析，免疫印迹和免疫细胞化学。此外，我们发现Olig 2诱导的分化诱导Dickkopf-1（Dkk 1）的表达，Dkk 1是Wnt信号传导的有效拮抗剂。Dkk 1处理以剂量依赖性方式阻断HB1.F3中的Wnt信号传导，并诱导分化为星形胶质细胞、少突胶质细胞和神经元。我们的研究结果支持肿瘤干细胞假说，即干细胞自我更新和增殖的信号通路一直维持到分化的晚期。在我们提出的模型中，Dkk 1可能在下调干细胞分化后期的自我更新和增殖途径中发挥重要作用，其失败可能导致癌变。
Understanding stem cell-differentiation at the molecular level is important for clinical applications of stem cells and for finding new therapeutic approaches in the context of cancer stem cells. To investigate genome-wide changes involved in differentiation, we have used immortalized neural stem cell (NSC) line (HB1.F3) and Olig2-induced NSC differentiation model (F3.Olig2). Using microarray analysis, we revealed that Olig2-induced NSC differentiation involves downregulation of Wnt pathway, which was further confirmed by TOPflash/FOPflash reporter assay, RT-PCR analysis, immunoblots, and immunocytochemistry. Furthermore, we found that Olig2-induced differentiation induces the expression of Dickkopf-1(Dkk1), a potent antagonist of Wnt signaling. Dkk1 treatment blocked Wnt signaling in HB1.F3 in a dosage-dependent manner, and induced differentiation into astrocytes, oligodendrocytes, and neurons. Our results support cancer stem cell hypothesis which implies that signaling pathway for self-renewal and proliferation of stem cells is maintained till the late stage of differentiation. In our proposed model, Dkk1 may play an important role in downregulating self-renewal and proliferation pathway of stem cells at the late stage of differentiation, and its failure may lead to carcinogenesis.
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