Promoter-specific regulation of the brain-derived neurotropic factor gene by thyroid hormone in the developing rat cerebellum

Thyroid hormone (TH) plays a critical role in normal cerebellar development . However, the molecular mechanisms of TH action in the developing cerebell um are not fully understood. This action could be exerted in part through b rain-derived neurotropic factor (BDNF), as cerebellar BDNF messenger RNA (m RNA) expression is lower, and replacement of BDNF partially reverses the ab normal neurogenesis in the hypothyroid rat. The rat BDNF gene consists of f our noncoding exons (exons I-TV), each of which is linked to a different pr omoter, and a protein-coding exon (exon V). To study promoter-specific regu lation of the BDNF gene by TH, ribonuclease protection assay of each exon m RNA was performed using total developing rat cerebellar RNA. During cerebel lar development, all exon mRNAs were detected, but with different expressio n patterns; among noncoding exon mRNAs, exon II mRNA was the most abundant. Daily TH replacement induced a 3-fold increase in exon II mRNA on postnata l day (P) 15. On P30, exon II mRNA was still much greater in the TH-replace d animal. Exon I mRNA was detected on P2 and P7. However, in contrast to ex on II mRNA, TH treatment suppressed the expression of exon I mRNA. on P2. E xon III and TV mRNAs were not detected on P2 and P7, but small amounts were observed starting on P15 in TH-replaced animals. They were not detected by P30 in hypothyroid animals. In contrast, in the cerebral cortex, although all exons are differentially regulated during: development, the expression of each mRNA was not significantly altered by TH. These results indicate th at TH regulates BDNF gene expression in a promoter-, developmental stage-, and brain region-specific manner, which may play an important role in regio n- and stage-specific regulation of brain development by TH.