Regulation of growth rate and developmental timing by Xenopus thyroid hormone receptor

Thyroid hormone (TH) is critical for vertebrate postembryonic development, a period around birth in mammals when plasma TH levels are high. Interestingly, TH receptors (TRs), especially TR, are expressed prior to the synthesis and secretion of zygotic TH, suggesting the existence of unliganded TR during development. However, the role of unliganded TR during mammalian development has been difficult to study, in part due to the relatively weak phenotype of TR knockout mice. Amphibian metamorphosis resembles postembryonic development in mammals and is controlled by TH via TRs. Like in mammals, TR gene is highly activated and is the major TR expressed prior to the synthesis of endogenous TH. By using TALEN (transcriptional activator like effector nucleases)-mediated gene editing approach, we and others have now shown that unliganded TR has two independent functions during Xenopus premetamorphosis, i.e. inhibiting growth rate and slowing development. Furthermore, molecular and transgenic studies have shown that unliganded TR accomplishes these via the recruitment of histone deacetylase (HDAC)-containing corepressor complexes to repress the expression of TH-inducible genes.