Thyroid hormone (T3) is essential for brain development and most of its actions are exerted at the gene expression level after interaction with nuclear receptors. In particular, genes encoding cytoskeletal proteins are influenced by the thyroidal status. Thyroid hormone is involved in the normal downregulation of the Talpha1 alpha-tubulin gene during postnatal growth. The action of T3 on Talpha1 tubulin expression is complex and is exerted at least at two levels. In cultured cells, T3 induces a transient and fast decrease of Talpha1 mRNA concentration. This effect is enhanced when transcription is blocked by actinomycin D, suggesting that T3 increases mRNA degradation. In transgenic animals T3 affects the expression of beta-galactosidase under control of the Talpha1 promoter in the same way as the endogenous gene, supporting an effect mediated through the Talpha1 promoter. However, the Talpha1 promoter is not regulated by T3 in transfected cells and, therefore, the effects of the hormone in vivo are likely to be indirect. It is concluded that regulation of Talpha1 alpha-tubulin by thyroid hormone is the result of multiple influences including effects on mRNA half life and indirect effects at the promoter level.