Divide and Thrive: Unravelling the unconventional dynamics and regulation of rapidcell division during Plasmodium male gamete formation

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Cell division is the central process enabling organisms to proliferate, propagate and survive. Extensive fundamental understanding of cell division mechanisms exist in model eukaryotes like mammalian and yeast systems. Such studies are limited for evolutionarily divergent organisms, such as Plasmodium - the causative agent of malaria - as these species are often more complex or difficult to study. In Plasmodium, male gamete formation occurs by a rapid atypical cell division process within fifteen minutes, compared to many hours in model eukaryotes. Here, genome replication from 1N to 8N takes place with successive spindle formation, chromosome segregation in the nucleus and concomitant axoneme and unusual flagella assembly in the cytoplasm, allowing eight flagellated haploid gametes to be formed in fifteen minutes. This rapidity suggests novel mechanisms control the cell cycle and the microtubule organising centre (MTOC) compared to standard model eukaryotes. Consistent with the unusual nature of this cell division, many canonical regulators like mitotic protein kinases are either missing or highly divergent in Plasmodium. This life cycle stage occurs within the mosquito and is essential for parasite transmission. The proposal aims to unravel how cell division during male gamete formation is governed by the divergent mitotic protein kinases, and dissect the timing of assembly and function of the MTOC, mitotic spindle and axoneme components. We will use real time live cell imaging, genetic modulation of kinase function, phosphoproteomics, protein network analysis and three-dimensional electron microscopy to decipher spatial organisation, function and ultrastructure of the different components. This will deliver a new integrated, holistic view of parasite cell division and broaden our understanding and importance of evolutionarily conserved and divergent mechanisms of cell division. The study will also help to reveal potential targets for intervention of malaria