Microtubule (Mt) populations show large differences in dynamic properties (i.e., turnover rates) among cell types, and even within the same cell type at different stages of the cell cycle or stages of differentiation. These differences in dynamic properties are correlated with altered sensitivity to Mt-disassembling drugs (e.g. colchicine) which bind specifically to the Mt protein tubulin and to certain toxic metals which also interact with tubulin (e.g. methylmercury) and result in Mt disassembly. Mts in neurons become progressively more stable and more resistant to such compounds during differentiation. We are using the P19 embryonal carcinoma cell line, which can be induced to differentiate along the neural pathway by retinoic acid, as a model system in which to analyze the development of stable Mts. Our results show that during differentiation there is an evolution in the sorting of tubulin isotypes into the stable Mts. This appears related both to the expression of specific Mt-associated proteins and to concomitant posttranslational modifications of tubulin.