Gene-free methodology for cell fate dynamics during development.
Gene-free methodology for cell fate dynamics during development.
复制标题
发育过程中细胞命运动态的无基因方法。
DOI：
10.7554/elife.30743
复制
发表时间：
2017-12-13
期刊：
影响因子：
7.7
通讯作者：
Siggia ED
中科院分区：
文献类型：
--
作者：
Corson F;Siggia ED
为每个基因分配一个变量的细胞功能模型经常导致具有许多参数的方程组，其行为是模糊的。几何模型将动态减少到直观的图形元素，为稀疏的体内数据和发育过渡的透明描述提供紧凑的表示。为了说明，一个几何模型拟合秀丽隐杆线虫外阴发育，意味着一个相图，其中细胞命运的选择显示在一个由EGF和Notch信号水平定义的平面。该图定义了EGF或Notch水平变化时允许和禁止的细胞命运转变，并解释了先前归因于这些信号的上下文依赖性作用的令人惊讶的观察结果。该图还揭示了信号水平的微小变化导致EGF和Notch之间强烈上位相互作用的特殊点的存在。我们的模型正确地预测了这些点附近的实验，并提出了信号中特定的时间扰动，这些扰动可能导致额外的意外结果。最初，胚胎由相同的细胞组成。然后，随着胚胎的发育，这些细胞分化成不同的类型，如心脏和脑细胞。细胞发送和接收的化学信号是在正确的时间和地点形成正确类型细胞的关键。产生和解释这些信号的细胞机制非常复杂，难以理解。在20世纪50年代，康拉德·沃丁顿提出了另一种思考方式，即非特化细胞如何发展成为许多不同命运之一。他建议将发育中的细胞想象成一个沿着沿着滚动的球。当球运动时，障碍物会引导它沿着沿着特定的路径运动。最终，球停在一个山谷里，风景中的每个山谷代表着不同的细胞命运。尽管这种“景观模型”是一个关于信号事件如何引导细胞特化的有吸引力的比喻，但尚不清楚它是否可以投入生产使用。线虫物种秀丽隐杆线虫的产卵器官被称为外阴，并且经常被那些想要了解更多关于器官如何发育的研究人员研究。外阴由少量相同的细胞发育而成，这些细胞具有三种可能的细胞命运。两种化学信号，称为表皮生长因子（EGF）和Notch，控制着这一特化过程。Corson和Siggia现在已经构建了一个简单的景观模型，可以重现外阴细胞类型的正常排列。当调整以描述影响EGF或Notch的基因突变的影响时，该模型可以预测同时影响两种信号的突变的结果。景观中细胞路径的曲折也可以解释几个非直观的细胞命运结果，这些结果被认为是由EGF和Notch信号的微妙调节引起的。景观模型应易于应用于其他发育中的组织和器官。通过提供信号如何塑造细胞决策的直观图片，这些模型可以帮助研究人员学习如何控制细胞和组织发育。这可能会导致新的治疗方法来修复或替换衰竭的器官，使再生医学成为现实。
Models of cell function that assign a variable to each gene frequently lead to systems of equations with many parameters whose behavior is obscure. Geometric models reduce dynamics to intuitive pictorial elements that provide compact representations for sparse in vivo data and transparent descriptions of developmental transitions. To illustrate, a geometric model fit to vulval development in Caenorhabditis elegans, implies a phase diagram where cell-fate choices are displayed in a plane defined by EGF and Notch signaling levels. This diagram defines allowable and forbidden cell-fate transitions as EGF or Notch levels change, and explains surprising observations previously attributed to context-dependent action of these signals. The diagram also reveals the existence of special points at which minor changes in signal levels lead to strong epistatic interactions between EGF and Notch. Our model correctly predicts experiments near these points and suggests specific timed perturbations in signals that can lead to additional unexpected outcomes. At first, embryos are made up of identical cells. Then, as the embryo develops, these cells specialize into different types, such as heart and brain cells. Chemical signals sent and received by the cells are key to forming the right type of cell at the right time and place. The cellular machinery that produces and interprets these signals is exceedingly complex and difficult to understand. In the 1950s, Conrad Waddington presented an alternative way of thinking about how an unspecialized cell progresses to one of many different fates. He suggested visualizing the developing cell as a ball rolling along a hilly landscape. As the ball travels, obstacles in its way guide it along particular paths. Eventually the ball comes to rest in a valley, with each valley in the landscape representing a different cell fate. Although this “landscape model” is an appealing metaphor for how signaling events guide cell specialization, it was not clear whether it could be put to productive use. The egg-laying organ in the worm species Caenorhabditis elegans is called the vulva, and is often studied by researchers who want to learn more about how organs develop. The vulva develops from a small number of identical cells that adopt one of three possible cell fates. Two chemical signals, called epidermal growth factor (EGF) and Notch, control this specialization process. Corson and Siggia have now constructed a simple landscape model that can reproduce the normal arrangement of cell types in the vulva. When adjusted to describe the effect of genetic mutations that affect either EGF or Notch, the model could predict the outcome of mutations that affect both signals at once. The twists and turns of cell paths in the landscape could also account for several non-intuitive cell fate outcomes that had been assumed to result from subtle regulation of EGF and Notch signals. Landscape models should be easy to apply to other developing tissues and organs. By providing an intuitive picture of how signals shape cellular decisions, the models could help researchers to learn how to control cell and tissue development. This could lead to new treatments to repair or replace failing organs, making regenerative medicine a reality.