A novel pathway of cell cycle activation in root formative divisions

我们在学校里都学到，繁殖是生命的基本属性，生物体的细胞也是如此。所有的细胞都是由母细胞分裂而来的.通常，一个细胞分裂成两个相同类型的细胞，从而增加了种群规模。我们称之为“增殖分裂”，这在肿瘤中很容易理解，因为肿瘤中有许多相同的细胞。然而，当一个复杂的生物体正在发育时，例如胚胎从一个最初的受精卵细胞生长，必须产生新的细胞类型。这些问题产生于一种特殊的划分，称为“形成性划分”。在这种情况下，一个子细胞（或有时两个子细胞）与它们的母细胞不同，并具有新的身份。这种形成性分裂的过程对于干细胞的维持和功能也是必不可少的--这些细胞在体内可以进行形成性分裂，产生另一个干细胞和一个不同身份的新细胞。我们对调节增殖细胞分裂过程的分子有很多了解，部分原因是它们在癌症中的重要性。细胞分裂过程的分子和细胞方面被称为“细胞周期”。然而，我们对细胞周期中形成性分裂的不同机制所知甚少，甚至不知道是否存在不同的机制。我们一直在研究一种叫做拟南芥的植物根部的一种特殊类型的形成性分裂。我们研究植物是因为细胞不会四处移动，而且细胞的身份很容易确定，因为它是由它在根中的位置决定的。我们使用拟南芥是因为它生长迅速，有大量的早期研究可以借鉴，而且有很多资源可以使研究快速且相对便宜。根也是薄而透明的，因此我们可以使用共聚焦显微镜研究活根，这使我们能够可视化细胞分裂时蛋白质和基因的作用。根由同心圆的细胞层组成，每一层都有不同的特性，围绕着一个传导水分和养分的中心核心，我们所研究的特殊分裂涉及其中两层的形成，皮层和内皮层来自一层根的基本组织。内皮层是一个重要的组织，因为它形成了一个不可渗透的层，控制水和离子进入中央传导组织的运动。没有内皮层，根就不能正常生长和发挥功能。这正是一种叫做短根的基因突变体所发生的情况。在这种突变体中，形成性分裂不发生。我们与美国一个领先研究小组合作，在去年发表在《自然》杂志上的一篇论文中表明，SHORT-ROOT直接控制一种名为细胞周期蛋白D 6的细胞周期调节基因的表达，该基因仅在进行形成性分裂的细胞中开启。如果细胞周期蛋白D 6缺失，则形成性分裂没有得到适当的控制。细胞周期蛋白与一种称为细胞周期蛋白依赖性激酶的蛋白质协同工作。现在已经确定了这一点，该基因的突变体在形成性分裂中也有缺陷，证实它也参与其中。这两种蛋白质通常不会一起工作，因此我们相信我们已经确定了一种新的机制，通过这种机制，细胞周期在形成性分裂中被打开，这也涉及我们已经确定的第三种候选物。在本项目中，我们将详细分析这种新机制。我们认为它涉及三个相互激活的反馈回路，因此为了理解它们，我们将使用数学建模来预测对系统进行更改的影响，并测试这些预测。我们将与美国、荷兰和英国的世界领先团体合作开展这项工作，为解决这一问题带来卓越的专业知识。

We all learn at school that reproduction is a fundamental property of life, and the same is true of the cells from which organisms are built. All cells arise from a parent cell by division. Usually a cell divides to make two cells of the same type, increasing the population size. We refer to this as a "proliferative division", and is easy to think about in a tumour where there are many identical cells. However, when a complex organism is developing, for example as an embryo grows from a single initial fertilised egg cell, new cell types have to be produced. These arise from a special kind of division, known as a "formative division". In this case one daughter cell (or sometimes both daughter cells), are different from their parent cell and have a new identity. This process of formative division is also essential in the maintenance and function of stem cells- these are cells in the body that can undergo formative divisions to generate another stem cell and a new cell of different identity.We know a lot about the molecules that regulate the processes of proliferative cell divisions, in part because of their importance in cancer. The molecular and cellular aspects of the process of cell division are known as the "cell cycle". However we know very little about what different mechanisms operate in the cell cycle of formative divisions or indeed even if there are different mechanisms. We have been studying a particular type of formative division in the root of a plant called Arabidopsis. We study plants because the cells do not move around, and the identity of a cell is easy to establish because it is determined by its position in the root. We use Arabidopsis because it grows rapidly, there is a great wealth of earlier studies to draw on, and there are a lot of resources that make the research fast and relatively cheaper. The roots are also thin and transparent so we can study living roots using a confocal microscope that allows us to visualise the action of proteins and genes as cells divide. The root consist of concentric layers of cells, each layer with a different identity, wrapped around a central core that conducts water and nutrients.The particular division we have been studying involves the formation of two of these layers, the cortex and endodermis from a single layer of root ground tissue. The endodermis is a crucial tissue because it forms an impermeable layer controlling the movement of water and ions into the central conducting tissue. Without the endodermis the root cannot grow and function properly. This is exactly what happens in mutants of a gene called SHORT-ROOT. In this mutant, the formative divisions do not take place. In collaboration with a leading US group, we showed in a paper published last year in the journal "Nature" that SHORT-ROOT directly controls expression of a cell cycle regulating gene called cyclin D6, which is only switched on in cells carrying out the formative division. If cyclin D6 is missing, the formative division is not properly controlled. Cyclins work together with a partner protein called a cyclin-dependent kinase. This has now been identified, and mutants in this gene also have a defect in the formative division, confirming it is also involved. These two proteins do not normally work together, so we believe that we have identified a new mechanism by which the cell cycle is switched on in formative divisions, which also involves a third candidate we have identified. In this project, we will analyse this new mechanism in detail. We think it involves three feedback loops that all activate each other, so to understand them, we will use mathematical modelling to predict the effect of making changes to the system and test these predictions. We will carry out the work in collaboration with world-leading groups in the US, Holland and the UK, bringing exceptional expertise to bear on this problem.