Corepressor requirement and thyroid hormone receptor function during Xenopus development.

The biologic role of hormonal activation of nuclear receptors is well established. Only recently, however, has the biologic significance of repression begun to be appreciated. Amphibian metamorphosis is marked by dramatic thyroid hormone induced changes, including de novo morphogenesis, tissue remodeling, and organ resorption through programmed cell death. These changes involve cascades of gene regulation initiated by 3,5,3'-triiodothyronine (T(3)). T(3) functions by regulating gene expression through thyroid hormone receptor (TR). TRs are DNA-binding transcription factors that belong to the steroid hormone receptor superfamily. In the absence of a ligand, TRs can repress gene expression by recruiting corepressor complexes, whereas liganded TRs recruit coactivator complexes for gene activation. Corepressor and coactivator complexes induce chromatin remodeling to mediate TR regulation of transcription. The mechanisms of TR action permit a dual function for TRs during development. In premetamorphic tadpoles, when TRs are expressed and T(3) levels are barely detectable, unliganded TRs repress transcription through corepressor recruitment. This TR-mediated repression of target genes is critical for proper larval development, allowing tadpole growth and acquisition of metamorphic competence. In contrast, during metamorphosis, endogenous T(3) causes TRs to activate gene expression, leading to tadpole transformation. Several results also support a role for corepressors during metamorphosis. Corepressor targeted functions, however, are still speculative but may again involve TRs. The requirement of active gene repression at different stages during amphibian development establishes an important biologic role for corepressors.