Thyroid hormones and brain development

The action of thyroid hormones (thyroxine, T4; triiodothyronine, T3) on brain development and function is gaining renewed interest. It has been known for many years that thyroid hormones are very important in mammalian brain maturation, influencing many aspects related to neural cell migration, differentiation, and signaling. In the last 10 years, genes regulated by thyroid hormones have been identified in the rodent brain, and understanding of the role of thyroid hormone nuclear receptors has been facilitated with the analysis of the phenotype of mutant mice for the different receptor isoforms. The general picture that emerges is that T4 and T3 may enter the brain through specific transporters. T4 is converted to the active hormone, T3, in glial cells, astrocytes, and tanycytes, although the main target cells are neurons and maturing oligodendrocytes. T3, acting through the nuclear receptors, controls the expression of genes involved in myelination, cell differentiation, migration, and signaling. In addition to transducing the T3 signal, the nuclear receptors also have activity in the unliganded state (i.e., as aporeceptors), mainly as repressors of transcription. The physiological meaning of aporreceptor action is not known, but they may play a role in the genesis of the hypothyroid phenotype. Among the questions that remain to be explored in more detail is the role of thyroid hormones and the T3 receptors, both liganded and unliganded, in the fetal brain, especially before onset of fetal thyroid gland function. These questions are relevant for human health and the management of thyroid diseases during pregnancy.