A novel pathway of cell cycle activation in root formative divisions

根形成分裂中细胞周期激活的新途径

• 批准号: BB/J009199/1
• 负责人: James Murray
• 金额: $ 85.84万
• 依托单位: CARDIFF UNIVERSITY
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ009199%2F1
• 关键词: novel; pathway; cell; cycle; activation

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.

我们在学校里都学到，繁殖是生命的基本属性，构成生物体的细胞也是如此。所有的细胞都是由亲本细胞分裂而产生的。通常一个细胞分裂成两个相同类型的细胞，增加种群的大小。我们称之为“增殖性分裂”，在有许多相同细胞的肿瘤中，这很容易理解。然而，当一个复杂的有机体正在发育时，例如，当一个胚胎从一个单一的初始受精卵细胞生长出来时，必须产生新的细胞类型。这些源自一种特殊的划分，称为“形成性划分”。在这种情况下，一个子细胞（有时是两个子细胞）与它们的亲本细胞不同，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——干细胞是体内可以经历形成性分裂以产生另一个干细胞和具有不同身份的新细胞的细胞。我们对调节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。细胞分裂过程的分子和细胞方面被称为“细胞周期”。然而，我们对细胞形成分裂周期中不同的机制所知甚少，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分裂。我们研究植物是因为细胞不会到处移动，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，因为它生长迅速，有大量的早期研究可以借鉴，有很多资源使研究快速和相对便宜。根也很薄，透明，所以我们可以用共聚焦显微镜研究活根，这使我们能够看到蛋白质和基因在细胞分裂时的作用。根由同心圆的细胞层组成，每一层都有不同的特征，围绕着一个传导水和营养物质的核心。我们一直在研究的这种特殊的分裂涉及到两层的形成，皮层和内胚层，来自于一层根底组织。内胚层是一个至关重要的组织，因为它形成一个不渗透的层，控制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功能。这正是一种叫做SHORT-ROOT的基因突变所发生的情况。在这个突变体中，形成性的分裂没有发生。我们与一个领先的美国研究小组合作，在去年发表在《自然》（Nature）杂志上的一篇论文中表明，SHORT-ROOT直接控制一种叫做cyclin D6的细胞周期调节基因的表达，这种基因只在进行形成性分裂的细胞中启动。如果缺少周期蛋白D6，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伙伴蛋白一起工作。现在已经确定了这一点，该基因的突变体在形成分裂中也有缺陷，证实了它也参与其中。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开启，这也涉及到我们已经确定的第三种候选蛋白。在本项目中，我们将详细分析这一新机制。我们认为它包括三个相互激活的反馈回路，因此为了理解它们，我们将使用数学模型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团队合作开展这项工作，为这一问题带来卓越的专业知识。

项目成果

Phytotracker, an information management system for easy recording and tracking of plants, seeds and plasmids.

• DOI: 10.1186/1746-4811-8-43
• 发表时间: 2012-10-13
• 期刊: Plant methods
• 影响因子: 5.1
• 作者: Nieuwland J;Sornay E;Marchbank A;de Graaf BH;Murray JA
• 通讯作者: Murray JA

Cell-size dependent progression of the cell cycle creates homeostasis and flexibility of plant cell size.

• DOI: 10.1038/ncomms15060
• 发表时间: 2017-04-27
• 期刊: Nature communications
• 影响因子: 16.6
• 作者: R Jones A;Forero-Vargas M;Withers SP;Smith RS;Traas J;Dewitte W;Murray JAH
• 通讯作者: Murray JAH

The Arabidopsis CDK inhibitor ICK3/KRP5 is rate limiting for primary root growth and promotes growth through cell elongation and endoreduplication.

• DOI: 10.1093/jxb/ert009
• 发表时间: 2013-02
• 期刊: Journal of experimental botany
• 影响因子: 6.9
• 作者: Wen B;Nieuwland J;Murray JA
• 通讯作者: Murray JA

Re-induction of the cell cycle in the Arabidopsis post-embryonic root meristem is ABA-insensitive, GA-dependent and repressed by KRP6.

• DOI: 10.1038/srep23586
• 发表时间: 2016-03-29
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Nieuwland J;Stamm P;Wen B;Randall RS;Murray JA;Bassel GW
• 通讯作者: Bassel GW

WOX5 suppresses CYCLIN D activity to establish quiescence at the center of the root stem cell niche.

• DOI: 10.1016/j.cub.2014.07.019
• 发表时间: 2014-08-18
• 期刊: CURRENT BIOLOGY
• 影响因子: 9.2
• 作者: Forzani, Celine;Aichinger, Ernst;Sornay, Emily;Willemsen, Viola;Laux, Thomas;Dewitte, Walter;Murray, James A. H.
• 通讯作者: Murray, James A. H.