Endocrine Abstracts

Thyroid hormone T3 controls many functions in Vertebrates including developmental processes (body and skeletal growth, nervous system maturation) and physiological regulations (heart rate, thermogenesis, glycemia, T3 production). The action of T3 is mediated by two isotypes of nuclear receptors, respectively TRa and TRb that are encoded by two different genes. Each of these two genes encodes several isoforms, several of which are not true receptors.

T3 is known to be essential for early steps of post natal development in Human and rodents. Mice devoid of TRa receptors show strong alterations in the development of intestine, bone, and hematopoiesis. Mice missing TRb receptors show alterations in the development of brain and neurosensory functions. To investigate in more details the roles of thyroid hormone in the development, we used mutant mice with a knock-out of the Pax8 gene (Pax8-/- mice). These mice do not develop functional thyroid follicles and are congenitally hypothyroid. They die during the weaning period.

Surprisingly the Pax8-/- mice show a much more severe phenotype than mice double knock-out for both TRa and TRb genes. These data show that lack of hormone is much more deleterious than the lack of receptors. When we inactivated the TRa but not the TRb gene in the Pax8-/- mice we could observe a survival of the animals and a strong recovery in the phenotype of various tissues including bone, intestine and spleen. Biochemical analyses on gene expression in the compound mutant mice strongly suggested that the lethality of the Pax8-/- mice is due to the repressive effect of TRa aporeceptors.

These data allow to propose a model in which the TRa receptors are playing major functions at the time of birth for the activation of genes necessary for the maturation of some organs. The TRa receptor appears then as a master switch for the post-natal development.