Stochastic hybrid systems approach to uncovering cell-size control mechanisms

增殖的真核细胞通过细胞大小与细胞分裂的耦合来积极地维持细胞大小的稳态。要做到这一点，细胞必须整合模拟信息（即细胞大小或大小的代理），并将其转换为数字“全或无”的分裂决定。虽然最近的工作为细菌和酵母的大小稳态策略提供了关键的见解，但真核生物的大小控制在动物和其他分类群中仍然知之甚少。该项目研究了一个独特的优势模型的大小控制，单细胞藻莱茵衣藻（Chlamydomonas reinhardtii），在G1期的长时间生长使单个细胞的大小增长到30倍。在G1末期，母细胞经历一系列快速交替的基因组复制和分裂，产生2n个大小一致的子细胞，其中n是分裂周期的次数。这种细胞周期与一些动物早期胚胎细胞周期具有共同的特征，并由在动物中具有同源物或相近类似物的调节因子控制。对分裂的承诺是如何发生的，以及衣藻细胞如何“计数”随后快速分裂周期的正确数量以实现细胞大小的稳态仍然是一个谜。

Proliferating eukaryotic cells actively maintain size homeostasis by coupling cell size to cell division. To do so cells must integrate analog information (i.e. cell size or a proxy for size) and convert it into a digital "all-ornone" decision to divide. While recent work has provided key insights into size homeostasis strategies in bacteria and yeasts, eukaryotic size control remains poorly understood in animals and other taxa. The project investigates size control in a uniquely advantageous model, the unicellular alga Chlamydomonas reinhardtii (Chlamydomonas), where prolonged growth in the G1 period allows individual cells to grow in size up to thirty-fold. At the end of G1, mother cells undergo a rapid series of alternating genome replications and divisions to produce 2n uniform-sized daughters, where n is the number of division cycles. This cell cycle has features in common with some animal early embryonic cell cycles and is controlled by regulators that have homologs or close analogs in animals. How commitment to division occurs, and how Chlamydomonas cells "count" the correct number of subsequent rapid division cycles to achieve cell size homeostasis has remained a mystery. Deterministic models, when applied to Chlamydomonas, are unable to recapitulate observed cell division behavior because they fail to capture stochastic effects. Our prior studies have found Stochastic Hybrid Systems (SHS) that integrate continuous dynamics with random discrete events, to be a powerful framework for modeling size of individual cells across multiple generations. Preliminary analysis of these systems have led to new mathematical results on the forms of coupling between cell size and timing of division essential for maintaining size homeostasis. Combining SHS based models with single-cell measurements of size and gene expression in wild type and cell-cycle mutants, this study will characterize biomolecular circuits mediating size control in Chlamydomonas.