The important role of thyroid hormone (l-triiodothyronine, T3 l-tetraiodothyronine, T4) in the growth and differentiation of many organs, including the central nervous system, is well known (Legrand, 1986 Oppenheimer and Schwartz, 1997). In particular, the development of the rodent cerebellum is severely affected by perinatal hypothyroidism (Legrand, 1979 Koibuchi and Chin, 1999). Although the mechanism of thyroid hormone action on cerebellar development is not fully understood, recent studies have provided new insights into its molecular mechanisms in this process.

Molecular mechanisms of thyroid hormone action: a general overview

Thyroid hormone exerts its major effect by binding to the nuclear thyroid hormone receptor, a ligand-regulated transcription factor (Chin and Yen, 1997), although thyroid hormone action at non-genomic sites such as mitochondria, plasma membrane, and cytoplasm has also been reported (Davis and Davis, 1997). Figure 19.1 shows the mechanism of thyroid hormone action at the nuclear level. Thyroid hormone receptor is bound to specific DNA sequences known as thyroid hormone-response elements. When thyroid hormone receptor binds to thyroid hormone response element, it interacts with retinoid X receptors to form heterodimers, which, in turn, bind to a number of coregulators such as corepressors and coactivators. The liganded thyroid hormone receptor/retinoid X receptor/ coregulator complex ultimately determines nuclear thyroid hormone action (Chin and Yen, 1997).

Nuclear thyroid hormone receptors are encoded by two genomic loci (alpha and beta). Each thyroid hormone receptor gene produces two variants as a result of alternative splicing and different promoter usage (Lazar, 1993). Thyroid hormone receptor alpha gene produces thyroid hormone receptor alpha1 and c-erbA alpha2, whereas thyroid hormone receptor beta gene produces thyroid hormone receptor beta1, and beta2 (Fig. 19.2).