Role of Thyroid Hormone Receptor Subtypes α and β on Gene Expression in the Cerebral Cortex and Striatum of Postnatal Mice

The effects of thyroid hormones (THs) on brain development and function are largely mediated by the control of gene expression. This is achieved by the binding of the genomically active T-3 to transcriptionally active nuclear TH receptors (TRs). T-3 and the TRs can either induce or repress transcription. In hypothyroidism, the reduction of T-3 lowers the expression of a set of genes, the positively regulated genes, and increases the expression of negatively regulated genes. Two mechanisms may account for the effect of hypothyroidism on genes regulated directly by T-3: first, the loss of T-3 signaling and TR transactivation, and second, an intrinsic activity of the unliganded TRs directly responsible for repression of positive genes and enhancement of negative genes. To analyze the contribution of the TR subtypes alpha and beta, we have measured by RT-PCR the expression of a set of positive and negative genes in the cerebral cortex and the striatum of TR-knockout male and female mice. The results indicate that TR alpha 1 exerts a predominant but not exclusive role in the regulation of positive and negative genes. However, a fraction of the genes analyzed are not or only mildly affected by the total absence of TRs. Furthermore, hypothyroidism has a mild effect on these genes in the absence of TR alpha 1, in agreement with a role of unliganded TR alpha 1 in the effects of hypothyroidism. (Endocrinology 154: 1940-1947, 2013)