Stimulation of the myelin basic protein gene expression by 9-cis-retinoic acid and thyroid hormone: activation in the context of its native promoter

Thyroid hormone plays an important role in brain development, in part by re gulating myelination. Previous studies have shown that the myelin basic pro tein (MBP) promoter is activated by thyroid hormone (T3) via a T3-response element (T3RE) at position -186. Surprisingly, although MBP levels are init ially 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 transien t 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 v itro. The 9cRA-dependent activation of the MBP promoter required the presen ce of both, the DNA binding and the ligand-dependent transactivation domain (AF-2) in RXR. Furthermore, as T3, 9cRA was able to stimulate MBP expressi on in the CG-4 cell line after differentiation to oligodendrocytes and incr eased the number of cells expressing the MBP protein in primary rat optic n erve,glial cell cultures. (C) 1999 Elsevier Science B.V. All rights reserve d.