Pombo P M, Barettino D, Ibarrola N, Vega S, Rodríguez-Peña A
Instituto de Investigaciones Biomédicas, CSIC, c/ Arturo Duperier, 4, 28029, Madrid, Spain.
Brain Res Mol Brain Res. 1999 Jan 22;64(1):92-100. doi: 10.1016/s0169-328x(98)00311-8.
Thyroid hormone plays an important role in brain development, in part by regulating myelination. Previous studies have shown that the myelin basic protein (MBP) promoter is activated by thyroid hormone (T3) via a T3-response element (T3RE) at position -186. Surprisingly, although MBP levels are initially decreased in hypothyroid neonates, they approach later control levels, in most brain regions, despite persistent hypothyroidism. We have studied the T3-independent transcriptional regulation of this gene, using transient transfection assays. We found that, in the absence of T3, the RXR ligand, 9-cis-retinoic acid (9cRA) was able to stimulate transcription of the MBP promoter in a dose-dependent manner. This activation was unaffected by the mutation or deletion of the T3RE and required DNA sequences located between positions -162/+60. Accordingly, this MBP promoter fragment bound RXR in vitro. The 9cRA-dependent activation of the MBP promoter required the presence of both, the DNA binding and the ligand-dependent transactivation domain (AF-2) in RXR. Furthermore, as T3, 9cRA was able to stimulate MBP expression in the CG-4 cell line after differentiation to oligodendrocytes and increased the number of cells expressing the MBP protein in primary rat optic nerve glial cell cultures.
甲状腺激素在大脑发育中起着重要作用，部分是通过调节髓鞘形成来实现的。先前的研究表明，髓鞘碱性蛋白（MBP）启动子可通过位于-186位置的甲状腺激素反应元件（T3RE）被甲状腺激素（T3）激活。令人惊讶的是，尽管甲状腺功能减退的新生儿中MBP水平最初会降低，但在大多数脑区，尽管甲状腺功能持续减退，其水平后来会接近对照水平。我们使用瞬时转染实验研究了该基因的非T3依赖性转录调控。我们发现，在没有T3的情况下，RXR配体9-顺式视黄酸（9cRA）能够以剂量依赖性方式刺激MBP启动子的转录。这种激活不受T3RE突变或缺失的影响，并且需要位于-162 / +60位置之间的DNA序列。因此，该MBP启动子片段在体外与RXR结合。MBP启动子的9cRA依赖性激活需要RXR中同时存在DNA结合结构域和配体依赖性反式激活结构域（AF-2）。此外，与T3一样，9cRA能够在分化为少突胶质细胞后刺激CG-4细胞系中的MBP表达，并增加原代大鼠视神经胶质细胞培养物中表达MBP蛋白的细胞数量。
