A novel pathway of cell cycle activation in root formative divisions

我们在学校都知道，繁殖是生命的基本属性，构成有机体的细胞也是如此。所有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，从而增加种群大小。我们将其称为“增殖性分裂”，在有许多相同细胞的肿瘤中很容易想到这一点。然而，当一个复杂的有机体正在发育时，例如胚胎从单个初始受精的卵细胞发育而来，就必须产生新的细胞类型。它们产生于一种特殊的分裂，被称为“形成性分裂”。在这种情况下，一个子代细胞(有时两个子代细胞)不同于它们的父代细胞，并具有新的身份。这种形成性分裂的过程对干细胞的维持和功能也是必不可少的--干细胞是体内的细胞，可以进行形成性分裂，产生另一种干细胞和不同身份的新细胞。我们对调控增殖细胞分裂过程的分子了解很多，部分原因是它们在癌症中的重要性。细胞分裂过程中的分子和细胞方面称为“细胞周期”。然而，我们对形成分裂的细胞周期中的不同机制知之甚少，甚至不知道是否存在不同的机制。我们一直在研究一种名为拟南芥的植物根部的一种特殊的形成性分裂。我们研究植物是因为细胞不会四处移动，而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供借鉴，而且有大量的资源使研究更快、更便宜。根也很薄，而且透明，所以我们可以用共焦显微镜来研究活的根，这让我们能够可视化细胞分裂时蛋白质和基因的行动。根由同心的细胞层组成，每一层都有不同的身份，包裹在传导水分和营养的中心核心上。我们一直在研究的特殊分裂涉及到其中两层的形成，皮层和内胚层来自一层根地面组织。内胚层是一个至关重要的组织，因为它形成了一个不渗透层，控制着水和离子进入中央传导组织的运动。没有内胚层，根就不能正常生长和发挥作用。这正是一种名为短根基因的突变体所发生的事情。在这个突变体中，不会发生形成性分裂。我们与美国一个领先的研究小组合作，在去年发表在《自然》杂志上的一篇论文中表明，短根直接控制细胞周期调节基因Cyclin D6的表达，该基因只在进行形成性分裂的细胞中打开。如果周期蛋白D6缺失，则说明形成期分裂没有得到适当的控制。细胞周期蛋白与一种叫做细胞周期蛋白依赖性激酶的伙伴蛋白协同工作。现在已经确定了这一点，该基因的突变在形成阶段也有缺陷，证实它也参与了这一过程。这两种蛋白质通常不会一起工作，所以我们相信我们已经确定了一种新的机制，通过这种机制，细胞周期在形成分裂中被开启，这也涉及到我们已经确定的第三个候选者。在本项目中，我们将对这一新机制进行详细分析。我们认为它涉及三个相互激活的反馈环路，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效果，并测试这些预测。我们将与美国、荷兰和英国的世界领先组织合作开展这项工作，为这一问题带来非凡的专业知识。

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.