TIP30 inhibits oligodendrocyte precursor cell differentiation via cytoplasmic sequestration of Olig1
TIP30 inhibits oligodendrocyte precursor cell differentiation via cytoplasmic sequestration of Olig1
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DOI：
10.1002/glia.22778
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发表时间：
2015-04
期刊：
影响因子：
6.2
通讯作者：
Wenjing Yang;Lin Xiao;Cui Li;Xiuyun Liu;Mingdong Liu;Qi Shao;Dan Wang;Aijun Huang;
中科院分区：
文献类型：
--
作者：
Wenjing Yang;Lin Xiao;Cui Li;Xiuyun Liu;Mingdong Liu;Qi Shao;Dan Wang;Aijun Huang;
少突胶质前体细胞的分化是中枢神经系统发育髓鞘形成和成人再髓鞘形成的先决条件。OPC分化的分子机制在很大程度上仍不清楚。在这里，我们证明了30 kDa的HIV-1 Tat相互作用蛋白(TIP30)是少突胶质细胞发育的负调控因子。TIP30−/−小鼠在出生后第14天和第21天显示出髓鞘蛋白水平升高。在OPC原代培养体系中，我们发现TIP30的过表达显著抑制了OPC的分化进程，而TIP30的敲除则显著促进了少突胶质细胞的分化。此外，在OPC分化的起始阶段，TIP30的过表达导致转录因子Opol1滞留在细胞质中，并减弱其核转位，而TIP30的敲除则导致更多的Olob1定位于细胞核。在铜酮诱导的脱髓鞘模型中，在再髓鞘形成过程中，胼胝体中NG2表达的细胞急剧增加，其核定位为Orig1。相反，在多发性硬化症的慢性脱髓鞘病变中，TIP30在NG2表达的细胞中异常表达，并且在这些细胞中很少观察到核寡核苷酸。综上所述，我们的研究结果表明，TIP30在少突胶质细胞分化中起着负向调节作用。Glia 2015；63：684-698
Differentiation of oligodendrocyte precursor cells (OPCs) is a prerequisite for both developmental myelination and adult remyelination in the central nervous system. The molecular mechanisms underlying OPC differentiation remain largely unknown. Here, we show that the thirty‐kDa HIV‐1 Tat interacting protein (TIP30) is a negative regulator in oligodendrocyte development. The TIP30−/− mice displayed an increased myelin protein level at postnatal day 14 and 21. By using a primary OPC culture system, we demonstrated that overexpression of TIP30 dramatically inhibited the stage progression of differentiating OPCs, while knockdown of TIP30 enhanced the differentiation of oligodendroglial cells remarkably. Moreover, overexpression of TIP30 was found to sequester the transcription factor Olig1 in the cytoplasm and weaken its nuclear translocation due to the interaction between TIP30 and Olig1, whereas knockdown of TIP30 led to more Olig1 localized in the nucleus in the initiation stage during OPC differentiation. In the cuprizone‐induced demyelination model, there was a dramatic increase in NG2‐expressing cells with nuclear location of Olig1 in the corpus callosum during remyelination. In contrast, within chronic demyelinated lesions in multiple sclerosis, TIP30 was abnormally expressed in NG2‐expressing cells, and few nuclear Olig1 was observed in these cells. Taken together, our findings suggest that TIP30 plays a negative regulatory role in oligodendroglial differentiation. GLIA 2015;63:684–698