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

细胞分裂是生物体增殖、繁殖和生存的中心过程。在哺乳动物和酵母系统等模式真核生物中，存在着对细胞分裂机制的广泛基础了解。这类研究仅限于进化上不同的生物，如疟疾的病原体疟原虫，因为这些物种往往更复杂或更难研究。在疟原虫中，雄配子的形成是通过快速的非典型细胞分裂过程在15分钟内发生的，而在模型真核生物中则需要数小时。在这里，从1N到8N的基因组复制发生了连续的纺锤体形成，染色体在核中分离，并伴随着轴丝和细胞质中不寻常的鞭毛组装，允许在15分钟内形成8个有鞭毛的单倍体配子。这一速度表明，与标准模型真核生物相比，控制细胞周期和微管组织中心(MTOC)的新机制。与这种细胞分裂的不同寻常的性质相一致的是，许多典型的调控因子，如有丝分裂蛋白激酶，在疟原虫中要么缺失，要么高度分化。这一生命周期阶段发生在蚊子体内，是寄生虫传播的关键。该提案旨在揭示雄配子形成过程中细胞分裂是如何由不同的有丝分裂蛋白激酶控制的，并剖析MTOC、有丝分裂纺锤体和轴丝组件的组装和功能的时机。我们将使用实时活细胞成像、激酶功能的遗传调节、磷酸蛋白质组学、蛋白质网络分析和三维电子显微镜来破译不同成分的空间组织、功能和超微结构。这将为寄生虫细胞分裂提供一个新的完整的整体观点，并拓宽我们对进化上保守的和不同的细胞分裂机制的理解和重要性。这项研究还将有助于揭示疟疾干预的潜在目标

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