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 correct ordering of sequential developmental events. A timing mechanism based on the number of mitotic divisions has been proposed for both higher eukaryote and protozoan parasite cellular differentiation. However, the mitotic clock model has not been validated by experiments which altered the proliferation rate of cells in vitro. This study has used the drugs aphidicolin and oxytetracycline to investigate the modulation of differentiation in the protozoan parasite Theileria annulata. The results showed that the timing of macroschizont to merozoite differentiation correlated with expression levels of a merozoite surface antigen during the reversible phase of the differentiation process. In addition, analysis of the effect of the drugs and elevation of culture temperature indicated that altered timing of differentiation was associated with changes to the rate of protein synthesis relative to DNA synthesis. From these results we postulate that the differentiation clock runs on the basis of a progressive elevation of a regulator(s) of merozoite gene expression to a quantitative commitment threshold. We also propose that this mechanism of timing can be corrupted by modulation of the proliferation potential (DNA synthesis) and/or growth potential (factor production) of the cell. The relevance of this model to differentiation in vivo and to other eukaryotic systems is discussed.