Murine models: new insights into physiology and pathophysiology of thyroidhormone receptors

Thyroid hormones are involved in vertebrate development and metabolic homeo stasis. Their actions are mediated through several nuclear receptors encode d by TR alpha and TR beta genes. The interspecies conservation of 3 functio nal receptors (TR alpha1,TR beta1 and TR beta2) and their partially distinc t tissue distribution suggest that they serve nonredundant physiological fu nctions. The exclusive TR beta gene involvement in the resistance to thyroi d hormone (RTH) reinforces the hypothesis of a functional specificity. Rece nt mouse knock-out and transgenesis methods allow invalidation or overexpre ssion of a gene of interest, respectively. They therefore provide powerful means to determine the specific function of a gene and have been applied to the thyroid hormone receptor genes. Mice TR beta (-/-) represent a model o f the recessive form of RTH. They have been shown to develop goiter and hig h thyroid hormone and TSH (Thyroid Stimulating Hormone) levels, suggesting an unique role for TR beta in the negative regulation of TSH pituitary secr etion. The associated disorder in audition maturation also showed that TR b eta plays an essential role in the development of audition. By contrast, mi ce TR alpha (-/-) exhibited thyroid gland atrophy along with decreased thyr oid hormones and TSH levels. Clinical phenotype included growth interruptio n and retardation of both intestine and bone maturation, but no hearing los s. Mice TR alpha beta (-/-) combined the disorders, including delayed neona tal development despite hyperactive hypothalamus-pituitary axis. Finally, t ransgenic overexpression of a mutant TR beta gene reproduced the dominant f orm of RTH and confirmed the major role of dominant negative activity in th e occurrence of some phenotypic key-features such as high circulating hormo ne levels despite high TSH levels, hyperactivity and lack of severe hearing loss. From these studies, it is suggested that TR alpha and TR beta recept ors are to some extent able to cooperate or substitute for each other. Howe ver some organs constitute TR-specific T3 target-tissues such as inner ear, pituitary, heart, liver, bone and small intestine.