Thyroid hormone receptors and their role in development

That most major physiological actions of thyroid hormones could be mediated via hormonal regulation of gene expression has been known for more than 25 years. The localization of TR in the cell nucleus, first reported almost 20 years ago, confirmed this concept. But it is only since the cloning of the TR gene and its identification as the c-erbA oncogene, accomplished 6 years ago, that we have begun to understand the details of the interaction between the hormone and its receptor and between the receptor and its target gene. Perhaps the most significant concept to emerge from the molecular studies is that the TR belongs to the superfamily of nuclear receptors for steroid hormones and morphogens such as retinoids. It highlights the evolutionary conservation of a major network of cellular signalling and intracellular regulatory pathways and which has helped bring us closer to a unified concept of the action of many growth and developmental hormones. Several important questions to be solved in the future become obvious from this brief review of the role of thyroid hormone in regulating developmental processes. Among these is the explantation for the high degree of tissue specificity of hormonal regulation of gene expression. The discovery of differential expression of the two major TR genes and the generation of multiple isoforms of the receptor by alternate splicing go some way to answering this question, but this is clearly not the sole factor determining tissue specificity. It will be most important to find out more about the interaction between the receptor and other transcription factors or nuclear proteins, some of which may be tissue specific and others expressed ubiquitously. The autoinduction of TR during amphibian metamorphosis, described above, emphasizes the intriguing question of how receptor genes are regulated during development. We know little as yet about the promoters and regulatory factors involved in this process. Finally, we have also described the recent recognition of genetic defects in TRs that underlie thyroid hormone linked diseases in humans. Future studies on the molecular genetics of receptors will enhance the importance in clinical practice of receptor linked diseases.