Asynchronous mitosis in multinucleate cells

描述（由申请人提供）：在从单细胞酵母到哺乳动物的生物体中，即使在相同的环境中生长，遗传上相同的细胞也表现出不同的细胞分裂周期时间。过程中可变性的来源和好处是未知的，例如为准确性而连接的细胞周期。特别是，它是不明白是否细胞周期的定时变异性是纯粹的随机或是否可以作为细胞周期电路的设计的一部分进行调节。其他细胞过程中的变异性已被证明是有益的，因此细胞周期的变异性实际上可能是一种适应性特征。多核丝状真菌，棉阿舒囊菌，是一个独特的模型系统，以研究细胞周期的时间变异性，因为核分裂异步在一个共同的细胞质。合胞体中的这种分裂需要细胞周期信号传导中的可变定时和核自主性。由于所有的蛋白质都在一个共同的细胞质中翻译，因此多个不同步的细胞周期振荡器如何共存是一个谜。我们正在利用这个模型系统中的异步分裂周期来发现细胞周期中是否存在可变性，并了解如何建立核自主性。变异性的分子基础的知识是必要的细胞周期控制和失调的细胞周期影响的病理学的完整理解。细胞周期决定的群体水平变异性可以影响真菌发病机制和肿瘤细胞行为等多种过程，并且可能是影响药物治疗功效的因素。虽然一些细胞间的变异性可以归因于转录中的分子噪音，但可以肯定的是，存在其他尚未确定的非遗传个体性细胞库。在这个建议中，我们结合联合收割机活细胞成像与计算和分子遗传学的方法，以确定来源的变异细胞周期，并确定如何建立核自主性。有了这个模型真菌系统，我们很好地定位，以确定保守的细胞周期变异性的来源，并了解如何细胞信号转导过程可以在一个共同的细胞质绝缘。该项目的具体目标是：1）确定G1持续时间的变化是随机的还是受调节的。2)检验细胞核大小控制细胞周期时间和变异性的假设。3)为了验证空间限制蛋白质运动产生核自主性的假设。几乎所有的细胞分裂周期都存在时间变异性，了解异质性的基础对于全面了解细胞周期至关重要。在这个项目中，我们将确定时间可变性是否在细胞分裂周期中编程，了解核大小如何控制时间以及细胞质如何在功能上划分以维持细胞分裂。

DESCRIPTION (provided by applicant): In organisms ranging from single-celled yeasts to mammals, genetically identical cells exhibit variable cell division cycle times even when growing in the same environment. The sources and benefits of variability in a process such as the cell cycle that is wired for accuracy are unknown. In particular, it is not understood whether cell cycle timing variability is purely stochastic or whether it may be regulated as part of the design of cell cycle circuits. Variability in other cell processes has been shown to be beneficial, so cell cycle variability may in fact be an adaptive trait. The multinucleate, filamentous fungus, Ashbya gossypii, is a unique model system to study cell cycle timing variability because nuclei divide asynchronously within a common cytoplasm. Such asynchrony in a syncytium requires variable timing and nuclear autonomy in cell cycle signaling. As all proteins are translated in a common cytoplasm, it is mysterious how multiple, out of sync, cell cycle oscillators can coexist. We are taking advantage of the asynchronous division cycle in this model system to discover whether variability is programmed into the cell cycle and to learn how nuclear autonomy can be established. Knowledge of the molecular basis for variability is necessary for a complete understanding of cell cycle control and the pathologies influenced by a misregulated cell cycle. Population level variability in cell cycle decisions can impact processes as diverse as fungal pathogenesis and tumor cell behavior, and may be a factor influencing the efficacy of pharmacological treatments. While some cell-to-cell variability can be attributed to molecular noise in transcription, it is certain that other, as yet unidentified, cellular reservoirs of non-genetic individuality exist. In this proposal, we combine live cell imaging with computational and molecular genetic approaches to identify sources of variability in the cell cycle and determine how nuclear autonomy is established. With this model fungal system, we are well positioned to identify conserved sources of cell cycle variability and learn how cell signaling processes can be insulated within a common cytoplasm. The specific aims of the project are: 1) To determine whether variability in G1 duration is stochastic or regulated. 2) To test the hypothesis that nuclear size controls cell cycle timing and variability. 3) To test the hypothesis that spatially restricted protein movement creates nuclear autonomy. Timing variability exists in nearly all cell division cycles and knowing the basis of heterogeneity is essential for a complete understanding of the cell cycle. In this project, we will determine if timing variability is programmed in the cell division cycle, learn how nuclear size controls timing and how the cytoplasm can be functionally compartmentalized to maintain asynchrony.