Microtubules are made from polymers of / dimers. We have observed in the rat liver that, on the first day after birth, -subunit is relatively high and -subunit, low, with respect to adult values. In the hypothyroid neonate, both subunits were found to be low, therefore indicating that thyroid hormone (TH) regulates these developmental changes. TH was also found to activate tubulin expression in the adult liver, especially -subunit. To investigate the role of thyroid hormone receptors (TRs) in tubulin expression, we analyzed mice lacking TR or TR in comparison with the wild type, in both normal and TH-deprived adult animals. The results suggest that, in vivo, -tubulin protein expression in the liver is primarily under TR positive control. In the euthyroid mice lacking TR, -tubulin expression was low. However, in the corresponding hypothyroid animals, it was found increased, therefore suggesting that the unliganded TR might also upregulate -tubulin expression. Accordingly, the TH administration to the hypothyroid TR-deprived mice reduced their high -tubulin expression. In parallel, the relatively high messenger level observed with these hypothyroid animals was reduced to the euthyroid level after T₃-treatment. The microtubular network of the mutant livers appeared, by immunofluorescence confocal microscopy, generally disorganized and drastically reduced in -tubulin in the mice lacking TR. In conclusion, our results indicate that -tubulin is critically controlled by TR in the liver, and that both TRs are probably needed in order to maintain the microtubular network organization of the liver.