Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity.
Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity.
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DOI：
10.1098/rsob.130132
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发表时间：
2014-01-22
期刊：
影响因子：
5.8
通讯作者：
Bakal C
中科院分区：
文献类型：
--
作者：
Sailem H;Bousgouni V;Cooper S;Bakal C
细胞生物学的一个目标是了解细胞如何适应不同的环境和细胞条件。要全面了解细胞形状与环境之间的关系，需要对响应外部线索和调节细胞骨架的信号网络有系统水平的了解。经典的生物化学和遗传学方法已经确定了数千种有助于细胞形状的单个组件，但由于它们在空间和时间上的相互作用的复杂性，仍然很难使用自下而上的方法预测这些组件的活动如何产生细胞形状。在这里，我们描述了使用自上而下的方法通过信号系统调节细胞形状。我们首先利用系统RNAi筛选产生的形状多样性，并全面定义迁移细胞探索的形状空间。我们提出了一个简单的布尔模型，涉及激活的Rac和Rho GTPases在两个隔间，以解释数据集中的所有细胞形状的基础。重要的是，我们还生成了一个概率图形模型，以显示细胞如何以确定性而不是随机的方式探索这个空间。我们使用活细胞成像验证了我们的模型所做的预测。我们的工作解释了Rho和Rac之间的串扰如何在遗传相同的群体中产生不同的细胞形状，从而产生形态异质性。
One goal of cell biology is to understand how cells adopt different shapes in response to varying environmental and cellular conditions. Achieving a comprehensive understanding of the relationship between cell shape and environment requires a systems-level understanding of the signalling networks that respond to external cues and regulate the cytoskeleton. Classical biochemical and genetic approaches have identified thousands of individual components that contribute to cell shape, but it remains difficult to predict how cell shape is generated by the activity of these components using bottom-up approaches because of the complex nature of their interactions in space and time. Here, we describe the regulation of cellular shape by signalling systems using a top-down approach. We first exploit the shape diversity generated by systematic RNAi screening and comprehensively define the shape space a migratory cell explores. We suggest a simple Boolean model involving the activation of Rac and Rho GTPases in two compartments to explain the basis for all cell shapes in the dataset. Critically, we also generate a probabilistic graphical model to show how cells explore this space in a deterministic, rather than a stochastic, fashion. We validate the predictions made by our model using live-cell imaging. Our work explains how cross-talk between Rho and Rac can generate different cell shapes, and thus morphological heterogeneity, in genetically identical populations.
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