Life Without Thyroid Hormone Receptor

Abstract Thyroid hormone (T3) is critical not only for organ function and metabolism in the adult but also for animal development. This is particularly true during the neonatal period when T3 levels are high in mammals. Many processes during this postembryonic developmental period resemble those during amphibian metamorphosis. Anuran metamorphosis is perhaps the most dramatic developmental process controlled by T3 and affects essentially all organs/tissues, often in an organ autonomous manner. This offers a unique opportunity to study how T3 regulates vertebrate development. Earlier transgenic studies in the pseudo-tetraploid anuran Xenopus laevis revealed that T3 receptors (TRs) are necessary and sufficient for mediating the effects of T3 during metamorphosis. Recent gene knockout studies with gene-editing technologies in the highly related diploid anuran Xenopus tropicalis showed, surprisingly, that TRs are not required for most metamorphic transformations, although tadpoles lacking TRs are stalled at the climax of metamorphosis and eventually die. Analyses of the changes in different organs suggest that removal of TRs enables premature development of many adult tissues, likely due to de-repression of T3-inducible genes, while preventing the degeneration of tadpole-specific tissues, which is possibly responsible for the eventual lethality. Comparison with findings in TR knockout mice suggests both conservation and divergence in TR functions, with the latter likely due to the greatly reduced need, if any, to remove embryo/prenatal-specific tissues during mammalian postembryonic development.