Abstract :
Among the diverse effects in the developing and mature animal influenced by thyroid hormone (TH) are brain ontogeny and function. Many of these effects are mediated at the level of gene transcription. Over the past decade, our knowledge of both the molecular mechanisms involved in this regulation and the nature of the involved TH receptors (TRs) and other factors has increased greatly. TH enters the cell to interact with nuclear TRs which, in turn, are bound to target DNA sequences known as TH-response elements (TREs). The TRs exist in a number of isoforms, TRα1, TRβ1 and TRβ2, with likely distinct functions, and are present in variable relative amounts in different tissues. For instance, TRβ2 is expressed largely in specific regions of the brain and pituitary gland. The major protein complex found on TREs is not a TR monomer or homodimer, but rather a TR heterodimer. The TR partner is generally a nuclear proteins(s) that is largely represented by a retinoid X receptor (RXR), a member of the nuclear receptor superfamily whose isoforms are also expressed in a marked tissue-specific pattern. It is likely that the liganded TR/RXR/TRE is the critical complex for the activation of gene expression. In addition, TREs exhibit a special feature, namely, the ability to silence positive TREs in the absence of ligand. A TR variant, TRα2, which is highly expressed in the brain, also shares this ability. Finally, it is now appreciated that TR function may be altered by other nuclear receptors such as the glucocorticoid, estrogen and progesterone receptors, and by posttranslational mechanisms such as phosphorylation, in potential molecular crosstalk. Together, these complex interactions of thyroid hormones, their receptors, and other nuclear proteins may serve to regulate a large array of different brain functions at the gene level and possibly lead to altered behavior.
