Stochastic hybrid systems approach to uncovering cell-size control mechanisms

增殖的真核细胞通过将细胞大小与细胞分裂耦合来积极维持大小稳态。为此，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“全或全”决定以进行分裂。虽然最近的工作为细菌和酵母的大小稳态策略提供了重要的见解，但对动物和其他类群的真核大小控制仍然知之甚少。该项目研究了单细胞藻类莱茵衣藻 (Chlamydomonas) 中独特优势模型的尺寸控制，其中 G1 期的延长生长允许单个细胞的尺寸增长高达 30 倍。在 G1 末期，母细胞经历一系列快速的交替基因组复制和分裂，产生 2n 个大小一致的子细胞，其中 n 是分裂周期数。该细胞周期与一些动物早期胚胎细胞周期具有共同特征，并由在动物中具有同系物或相近类似物的调节因子控制。如何进行分裂，以及衣藻细胞如何“计算”后续快速分裂周期的正确数量以实现细胞大小稳态仍然是个谜。 当应用于衣藻时，确定性模型无法重现观察到的细胞分裂行为，因为它们无法捕获随机效应。我们之前的研究发现，随机混合系统（SHS）将连续动态与随机离散事件相结合，是一个强大的框架，可以对多代个体细胞的大小进行建模。对这些系统的初步分析得出了关于细胞大小和分裂时间之间的耦合形式的新数学结果，这对于维持大小稳态至关重要。本研究将基于 SHS 的模型与野生型和细胞周期突变体中尺寸和基因表达的单细胞测量相结合，将表征衣藻中介导尺寸控制的生物分子回路。

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.