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Molecular and Cellular Endocrinology 246 (2006) 10–20

Amphibian metamorphosis as a model for the developmental actions of thyroid hormone
Jamshed R. Tata ∗
National Institute for Medical Research, Mill Hill, London NW7 2HA, UK

Abstract Thyroid hormone (TH) elicits multiple physiological actions in vertebrates from fish to man. These actions can be divided into two broad categories: thosewhere 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. Eachtissue 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 aretwo thyroid hormone receptors, TR and TR , 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 TR mRNA and protein are elevated 50–100 times during TH-induced metamorphic climax. This phenomenon of “autoinduction” of receptor is alsoseen 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 thestructure 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. © 2005 Elsevier Ireland Ltd. All rights reserved.
Keywords: Metamorphosis (amphibian); Thyroid hormone; Development; Triiodothyronine (T3 ); Thyroid receptor (TR); Programmedcell death (PCD)

1. Introduction An important feature of thyroid hormone (TH) is the broad multiplicity of its physiological actions in vertebrates, from fish to reptiles to amphibia to birds and mammals (Pitt-Rivers and Tata, 1959; Gorbman and Bern, 1962). As summarized in Table 1, these can be broadly divided into two classes of actions, according to whether the hormone regulates processes inadult life or when the organism is undergoing development. Thus, in adult mammals, TH controls basal metabolic rate and energy metabolism, while in most vertebrates it regulates metabolic processes involving nitrogen balance, lipid degradation, etc. In developing vertebrates, particularly during post-embryonic development, neurogenesis and all processes concerned with maturation of the centralnervous system are highly dependent on the availability of maternal or foetal TH, as exemplified by

cretinism, which is a well-known disorder of hormonal deficiency during human foetal development. So are morphological and functional maturation of many tissues, such as bone, liver, blood and skin in both warm- and cold-blooded vertebrates. But no developmental action of thyroid hormone is asdramatic as the initiation and progression of amphibian metamorphosis (Gilbert and Frieden, 1981; Gilbert et al., 1996; Tata, 1998; Shi, 1999). In this review, I shall illustrate how metamorphosis offers an ideal model system to understand cellular and molecular mechanisms underlying the action of TH during post-embryonic development. 2. Metamorphosis and its hormonal control Biologists had for long...
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