A novel pathway of cell cycle activation in root formative divisions

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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.