Cellular regulation of microtubule organization

Microtubules are constituents of axonemes, mitotic spindles, and elaborate arrays in interphase cells, and, with intermediate filaments and microfilaments, are among the most prevalent structures visualized in the cytomatrix (22, 44). With the exception ofthe A microtubule ofcilia and flagella, the lattice geometry ofmicrotubules is highly conserved . However, each of the major subunits of microtubules, aand a-tubulin, shows heterogeneity . The number ofaand f3-tubulin subspecies differs among tissues and organisms, and a number of types of analysis are used to examine how these tubulin variants are related to specific cell functions (1, 9-11, 33, 40) . Investigations of the number and complexity of genes coding for these polypeptides have also been initiated (see reference 13 for review) . However, the mechanisms that regulate the posttranslational compartmentalization of subunits, the spatial and temporal assembly of subunits into microtubules, and the integration of microtubules in various cellular events are still largely unknown . There are many levels at which the formation and organization of microtubules might be determined . A postulate originating from early analyses of mitotic spindle formation (32) was that a pool of subunits existed in equilibrium with formed microtubules; increases in the subunit concentration could therefore result in a net increase in polymer. With few exceptions, however, a rapid increase in the total tubulin pool does not appear to occur before the elaboration of more extensive microtubule arrays . For example, our studies (42, 50) have demonstrated that mouse neuroblastoma cells possessing microtubule-filled neurites contain four to five times more tubulin polymer than rounded, nondifferentiated cells, but the total tubulin content of these two cell types is the same . On the basis of volume calculations, the equilibrium concentration of subunits in the nondifferentiated cells is at least twice that in differentiated cells. Data such as this indicate that a simple equilibrium between subunit and polymer cannot account for the changes in microtubule formation coordinated with certain cellular events . In addition, recent findings show that an increase in the subunit concentration in cells, brought about either by drug treatment (15) or injection of tubulin (16), results in a depression of tubulin synthesis and the loss of tubulin mRNA. These data suggest that cells autoregulate the total tubulin pool and that this may be effected by "monitoring" of the monomer concentration (14) .