Secisbp2l对少突胶质细胞分化及髓鞘形成的调控机制研究

Oligodendrocytes are myelin-forming cells of the central nervous system. Thyroid hormone T3 is required for the differentiation and myelination of oligodendrocytes. The metabolism of T3 requires deiodinases. All deiodinases belong to selenoproteins. Previous studies supposed that translation of full-length and active selenoproteins requires selenocysteine insertion sequence binding protein 2 (Secisbp2), which helps decoding the stop coden “TGA” into selenocysteine residue. However, we found that the expression of Secisbp2 is undetectable in the spinal cord. Our preliminary study demonstrated that Secisbp2l, a paralogue of Secisbp2, is specifically expressed in oligodendrocyte. In addition, Secisbp2l can bind to the mRNA of deiodinases and promote their translation. Moreover, differentiation of oligodendrocytes were delayed in Secisbp2l conditional knockout mice. These results indicated that Secisbp2l is possibly an upstream regulator of T3 in the spinal cord. Secisbp2l may promote myelination via translational regulation of deiodinases. We will use conditional knockout of Secisbp2l in mice to study the effects and mechanism of Secisbp2l on regulating oligodendrocyte differentiation and myelination. This study will deepen our understanding of oligodendrocyte myelination regulation, and will provide us novel strategies for curing myelinogenesis disorders.

少突胶质细胞是中枢神经系统的髓鞘形成细胞，甲状腺激素T3对少突胶质细胞的分化和髓鞘形成具有重要的促进作用。T3的代谢依赖脱碘酶，而脱碘酶都是硒蛋白，早期的研究认为硒蛋白都需要硒代半胱氨酸结合蛋白Secisbp2将其阅读框中的终止密码子TGA翻译成硒代半胱氨酸，然而在脊髓中并无Secisbp2表达。Secisbp2l是Secisbp2的旁系同源物，我们发现，Secisbp2l在少突胶质细胞中特异性表达，并能与脱碘酶的mRNA结合并促进其翻译，Secisbp2l敲除小鼠少突胶质细胞分化受抑制。这就提示Secisbp2l很可能是T3的上游调节基因，其可能通过调节脱碘酶的翻译促进髓鞘形成。本项目中，我们将建立Secisbp2l的小鼠条件性敲除模型，来研究Secisbp2l对少突胶质细胞分化及髓鞘形成的作用及分子机制，扩展少突胶质细胞髓鞘形成的调控机制研究，为髓鞘形成障碍的治疗提供新思路。

甲状腺激素（TH）能够促进少突胶质细胞的及时分化。TH缺乏会导致少突胶质细胞的分化减少和髓鞘形成推迟以及智力迟钝。以前的研究表明，在中枢神经系统中，作为活性TH的T3主要是通过硒蛋白DIO2从其激素原即甲状腺素T4转化而来，而Dio2的mRNA主要在星形胶质细胞中表达，因此此前认为星形胶质细胞是中枢神经系统中T3的主要合成来源。然而，硒蛋白是一类特殊的蛋白，硒蛋白中含有硒代半胱氨酸，是由通常作为终止密码子的 UGA 编码的，这需要特殊的转录后调控才能完成。目前我们并不清楚DIO2在中枢神经系统发育过程中的时空合成调控。在这项研究中，我们发现SECISBP2L在处于分化阶段的少突胶质细胞中高表达，同时也是DIO2翻译的必要因子。通过在小鼠体内少突胶质细胞系特异性地敲除Secisbp2l，我们发现中枢神经系统中DIO2的蛋白含量下降，同时T3含量减少，伴随着小鼠少突胶质细胞分化减少，髓鞘形成不足和运动缺陷。进一步的实验表明，Secisbp2l条件敲除的小鼠中少突胶质细胞分化缺陷能够被T3及其类似物缓解，而不能被T4缓解。本研究结果提出了一条新的少突胶质细胞的分化的内在的自主调控机制，即少突胶质细胞能够通过 SECISBP2L-DIO2-T3这条通路自主合成T3并调控分化和髓鞘形成。