Divide and Thrive: Unravelling the unconventional dynamics and regulation of rapidcell division during Plasmodium male gamete formation
Lead Research Organisation:
University of Nottingham
Department Name: School of Life Sciences
Abstract
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
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
Organisations
Publications
Guttery DS
(2023)
Meiosis in Plasmodium: how does it work?
in Trends in parasitology
Hair M
(2023)
Atypical flagella assembly and haploid genome coiling during male gamete formation in Plasmodium.
in Nature communications
Zeeshan M
(2023)
Plasmodium ARK2 and EB1 drive unconventional spindle dynamics, during chromosome segregation in sexual transmission stages.
in Nature communications