Size Matters: A systems approach to understanding cell size control in a developing multicellular tissue

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Cells are the building blocks of tissues, but how 3D structures are built from cells is a fundamental unsolved problem in biology. It is even more complex when we consider a growing tissue, in which the physical properties of the building blocks (cells) change constantly as they grow and divide. We study the growing shoot tip or shoot meristem of the model plant Arabidopsis. This structure is required to produce new leaves and flowers as the plant grows. The early stages of organ development require efficient tissue growth and an increase in cell size is normally observed at this time. Over several years, we have developed techniques allowing us to image the meristem over extended periods in the confocal microscope. We can follow individual cells over time and determine their growth and division. In order to divide, a cell goes through a defined series of processes known as the cell cycle. Using fluorescent reporters we have developed, we can for the first time simultaneously determine the position of all cells in the cell cycle during imaging time courses of growing plant tissues. Our recently published study showed that the size cells reach when they divide is on average consistent for a given tissue and set of environmental conditions, but is highly plastic when these change. For example we found that cells were smaller, and tissue growth slower, when plants were grown under environmental conditions that restrict photosynthesis. Variation in cell size arises through unequal division and has to be removed. This is done by establishing a balance between growth and division on a cell by cell basis. The plasticity of the system leads us to consider that cell size at division is not determined by a direct "cellular ruler" but is instead determined as a consequence (or "emergent property") of the contributing processes of growth and division. This mechanism appears to be conserved from unicellular organisms which can also achieve a larger cell size and higher absolute growth rate under plentiful conditions. Regulation of cell size in these simple cells is achieved by balancing cell growth and division via the protein synthetic capacity of the cell. We have developed a model that can predict accurately the size of plant cells based on the rate of growth and the accumulation of activity of two regulatory proteins required for cell division (called CDKs) as the cell grows. We tested this extensively using different mutants and growth conditions and identified the key processes that lead to cell size control. These processes appear to be the production and thresholding of CDK activity. In this proposal we will identify the "sizer" molecules involved in these processes that establish the link between growth and division of cells and analyse their function using our state-of-the-art imaging and analysis techniques. We have a number of candidate sizers, with known roles in CDK regulation, but we will also carry out experiments to identify new candidates in an unbiased manner using a genome-wide approach based on identifying the rate at which proteins are being synthesized under different conditions. We will use a combination of experiments and mathematics to develop a model that will allow us to understand how these sizer molecules are regulated and what effect this has on cell size control.