Regulation of Nuclear Coactivator and Corepressor Expression in Mouse Cerebellum by Thyroid Hormone

Abstract

Thyroid hormone (TH) has an important role in central nervous system development. TH action is mediated by a number of transcription factors including thyroid hormone receptors (TRs) in combination with a group of coregulators that can either activate (coactivators) or repress (corepressors) transcription in the presence of TH. The aims of this report were to determine if regulation of the corepressor Hairless (Hr) by TH was TR-isoform- mediated in neonatal cerebellum and to determine if other cerebellar corepressors (SMRT and NCoR) and coactivators (SRC family) are also regulated by TH. In order to study this we examined 14-day-old and adult knockout mice that lack expression of the TRbeta or TRalpha isoforms and measured mRNA expression in untreated, hypothyroid and TH-treated young mouse pups. TH-treated wild-type and TRbeta-deficient mice demonstrated upregulation of Hr by 22.8- +/- 8.6- and 11.8- +/- 3.6-fold respectively, which was not upregulated in TRalpha-deficient mice. In wild-type mice, TH treatment results in a reciprocal decrease (61%) in the coactivator SRC-1. These changes were not observed in adult mouse cerebellum. No effect was seen with NCoR and SRC-3 expression. SMRT was 3-fold increased in TH treatment of only wild-type mouse pups. We conclude that (1) TRalpha is the major TR regulating Hr expression in the cerebellum of young mouse pups; (2) TH upregulates Hr and SMRT and downregulates SRC-1; (3) NcoR and SRC-3 may not be regulated by TH in the cerebellum at the transcriptional level; and (4) autoregulation of TH action may be mediated through TH-dependent expression of the cofactors necessary for TH action in the cerebellum and may be developmentally specific.