The present work investigates the role of thromboxane A(2) (TXA(2)) receptors in the development of oligodendrocytes (OLGs). The results demonstrate that the proteins of the TXA(2) signaling pathway, i.e., cyclooxygenase (COX-1), TXA(2) synthase (TS), and TXA(2) receptor (TPR) are expressed in the developing rat brain during myelination. Furthermore, culture of OLG progenitor cells (OPCs) revealed that the expression levels of these proteins as well as TXA(2) synthesis increase during OLG maturation. Separate studies established that activation of TPRs by the agonist U46619 increases intracellular calcium in both OPCs and OLGs as visualized by digital fluorescence imaging. Immunocytochemical staining demonstrated that TPRs are localized in the plasma membrane and perinuclear compartments in OPCs. However, during OLG differentiation, TPRs shift their localization pattern and also become associated with the nuclear compartment. This shift to nuclear localization was confirmed by biochemical analysis in cultured cells and by immunocytochemical analysis in developing rat brain. Finally, it was found that U46619 activation of TPRs in maturing OLGs resulted in enhanced myelin basic protein (MBP) expression. Alternatively, inhibition of endogenous TPR signaling led to reduced MBP expression. Furthermore, TPR-mediated MBP expression was found to be associated with increased transcription from the MBP promoter using a MBP-luciferase reporter. Collectively, these findings suggest a novel TPR signaling pathway in OLGs and a potential role for this signaling during OLG maturation and myelin production.

译文

:本工作调查了血栓烷A(2)(TXA(2))受体在少突胶质细胞(OLG)发育中的作用。结果表明TXA(2)信号通路的蛋白质,即环氧合酶(COX-1),TXA(2)合酶(TS)和TXA(2)受体(TPR)在发育中的大鼠脑中表达髓鞘化。此外,OLG祖细胞(OPC)的培养显示,OLG成熟期间这些蛋白质的表达水平以及TXA(2)合成增加。单独的研究表明,通过数字荧光成像可以看到,激动剂U46619对TPR的激活会增加OPC和OLG中的细胞内钙含量。免疫细胞化学染色表明,TPR位于OPC的质膜和核周区室中。但是,在OLG分化过程中,TPR会改变其定位模式,并且也与核区室相关联。这种向核定位的转变已通过培养细胞的生化分析和发育中的大鼠脑部的免疫细胞化学分析得到证实。最后,发现成熟的OLG中TPR的U46619激活导致髓鞘碱性蛋白(MBP)表达增强。或者,抑制内源性TPR信号传导导致MBP表达降低。此外,使用MBP-荧光素酶报道基因,发现TPR介导的MBP表达与从MBP启动子的转录增加有关。总的来说,这些发现表明OLG中存在一种新型的TPR信号通路,并且在OLG成熟和髓鞘生成过程中该信号的潜在作用。

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