MODULATION OF PROTEIN-SYNTHESIS RELATIVE TO DNA-SYNTHESIS ALTERS THE TIMING OF DIFFERENTIATION IN THE PROTOZOAN PARASITE THEILERIA-ANNULATA

The control of differentiation through time is critical for the correc t ordering of sequential developmental events. A timing mechanism base d on the number of mitotic divisions has been proposed for both higher eukaryote and protozoan parasite cellular differentiation. However, t he mitotic clock model has not been validated by experiments which alt ered the proliferation rate of cells in vitro. This study has used the drugs aphidicolin and oxytetracycline to investigate the modulation o f differentiation in the protozoan parasite Theileria annulata. The re sults showed that the timing of macroschizont to merozoite differentia tion correlated with expression levels of a merozoite surface antigen during the reversible phase of the differentiation process. In additio n, analysis of the effect of the drugs and elevation of culture temper ature indicated that altered timing of differentiation was associated with changes to the rate of protein synthesis relative to DNA synthesi s. From these results we postulate that the differentiation clock runs on the basis of a progressive elevation of a regulator(s) of merozoit e gene expression to a quantitative commitment threshold. We also prop ose that this mechanism of timing can be corrupted by modulation of th e proliferation potential (DNA synthesis) and/or growth potential (fac tor production) of the cell. The relevance of this model to differenti ation in vivo and to other eukaryotic systems is discussed.