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相结合来积极地维持大小的动态平衡。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替代物)，并将其转换为数字“全有或全无”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，但真核细胞的大小控制在动物和其他分类群中仍然知之甚少。该项目研究了一种独特的优势模型--单细胞藻类--莱茵衣藻(Chlamydomonas Rehardtii)的大小控制，在这种模型中，在G1期的长时间生长使单个细胞的大小增长到30倍。在G1期末，母细胞经历一系列快速交替的基因组复制和分裂，产生2n个大小一致的子代，其中n是分裂周期的数量。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或相近类似物的调节因子控制。衣藻细胞如何进行分裂，以及衣藻细胞如何计算随后快速分裂周期的正确数量，以实现细胞大小的动态平衡，仍然是一个谜。 当应用于衣藻时，确定性模型不能概括观察到的细胞分裂行为，因为它们未能捕捉到随机效应。我们之前的研究发现，随机混合系统(SHS)结合了连续动力学和随机离散事件，是模拟跨多代单个细胞大小的强大框架。对这些系统的初步分析已经导致了关于细胞大小和分裂时间之间的耦合形式的新的数学结果，这对于维持大小的动态平衡是必不可少的。将基于SHS的模型与野生型和细胞周期突变体中的大小和基因表达的单细胞测量相结合，这项研究将表征衣藻中调节大小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.