Intracellular thyroid hormone metabolism as a local regulator of nuclear thyroid hormone receptor-mediated impact on...

Thyroid hormones (THs) play an essential role in vertebrate development, acting predominantly via nuclear TH receptors (TRs) which are ligand-dependent transcription factors. Binding of the ligand (predominantly T3) induces a switch from gene activation to gene repression or vice versa. Iodothyronine deiodinases (Ds) and TH transporters are important regulators of intracellular T3 availability and therefore contribute to the control of TR-dependent development.

The present review discusses the possible roles of Ds and TH transporters in regulating embryonic and larval (pre-juvenile) TR-dependent development in vertebrates. It focuses mainly on well-known model species for direct and indirect vertebrate development, including zebrafish, Xenopus, chicken and mouse. Data are provided on stage- and tissue/cell-specific changes in expression of Ds and TH transporters. This information is combined with functional data obtained from gain-and-loss of function studies.

Knockout/knockdown of each type of D has provided strong evidence for their implication in the control of important developmental processes and several D expression patterns and functions have been conserved throughout vertebrate evolution. Knockout/knockdown of the inactivating D3 enzyme indicates that a premature switch from unliganded to liganded TR action is often more detrimental than a delayed one. The majority of ontogenetic studies on TH transporter distribution and function have focused on brain development, showing variable impact of knockout/knockdown depending on the species. Future research in different models using conditional silencing will hopefully further improve our understanding on how TH transporters, Ds and TRs cooperate to regulate TR-mediated impact on vertebrate development. This article is part of a Special Issue entitled: Nuclear receptors in animal development.