Amphibian metamorphosis as a model for the developmental actions of thyroid hormone.

Thyroid hormone (TH) elicits multiple physiological actions in vertebrates from fish to man. These actions can be divided into two broad categories: those where the hormone regulates developmental processes and those that involve actions in the adult organism. Amphibian metamorphosis is a most dramatic example of extensive morphological, biochemical and cellular changes occurring during post-embryonic development, which is obligatorily initiated and sustained by TH. It is, therefore, an ideal model system to understand the action of the hormone. Each tissue of the frog tadpole responds differently to TH, ranging from altered gene expression, morphogenesis, tissue re-structuring and extensive cell death, according to a developmental programme set in place before the thyroid gland begins to secrete the hormone. The key element determining the response to the hormone is the nuclear thyroid hormone receptor (TR). As in most vertebrates, there are two thyroid hormone receptors, TRalpha and TRbeta, which repress transcription in the absence of the ligand and whose concentration in the tissues is directly modulated by the hormone itself. In Xenopus, biochemical and in situ techniques have shown that the amount of TRbeta mRNA and protein are elevated 50-100 times during TH-induced metamorphic climax. This phenomenon of "autoinduction" of receptor is also seen with developmental or inductive processes regulated by other hormones acting through nuclear receptors. It is possible that receptor upregulation may be a pre-requisite for hormonal response. Recent molecular and cell biological studies have suggested that TRs function as multimeric complexes with other nuclear or chromatin proteins, such as co-repressors and co-activators, to regulate the structure of the chromatin, and thereby determine the transcription of the receptor-specified target gene. There is evidence that this may also be so for thyroid hormone regulated transcription during amphibian metamorphosis.