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Summary Chemical gradients can generate pattern formation in biological systems. In the fission yeast Schizosaccharomyces pombe , a cortical gradient of pom1p (a DYRK-type protein kinase) functions to position sites of cytokinesis and cell polarity and to control cell length. Here, using quantitative imaging, fluorescence correlation spectroscopy, and mathematical modeling, we study how its gradient distribution is formed. Pom1p gradients exhibit large cell-to-cell variability, as well as dynamic fluctuations in each individual gradient. Our data lead to a two-state model for gradient formation in which pom1p molecules associate with the plasma membrane at cell tips and then diffuse on the membrane while aggregating into and fragmenting from clusters, before disassociating from the membrane. In contrast to a classical one-component gradient, this two-state gradient buffers against cell-to-cell variations in protein concentration. This buffering mechanism, together with time averaging to reduce intrinsic noise, allows the pom1p gradient to specify positional information in a robust manner.

The antagonistic pleiotropy theory of aging proposes that aging takes place because natural selection favors genes that confer benefit early on life at the cost of deterioration later in life. This theory predicts that genes that impact development would play a key role in shaping adult lifespan. To better understand the link between development and adult lifespan, we examined the genes previously known to be essential for development. From a pool of 57 genes that cause developmental arrest after inhibition using RNA interference, we have identified 24 genes that extend lifespan in Caenorhabditis elegans when inactivated during adulthood. Many of these genes are involved in regulation of mRNA translation and mitochondrial functions. Genetic epistasis experiments indicate that the mechanisms of lifespan extension by inactivating the identified genes may be different from those of the insulin/insulin-like growth factor 1 (IGF-1) and dietary restriction pathways. Inhibition of many of these genes also results in increased stress resistance and decreased fecundity, suggesting that they may mediate the trade-offs between somatic maintenance and reproduction. We have isolated novel lifespan-extension genes, which may help understand the intrinsic link between organism development and adult lifespan. Key words: developmental arrest; antagonistic pleiotropy; aging; mRNA translation; mitochondria; C. elegans.

Cells can, in principle, control their size by growing to a specified size before commencing cell division. How any cell actually senses its own size remains poorly understood. The fission yeast Schizosaccharomyces pombe are rod-shaped cells that grow to ∼14 µm in length before entering mitosis. In this study, we provide evidence that these cells sense their surface area as part of this size control mechanism. We show that cells enter mitosis at a certain surface area, as opposed to a certain volume or length. A peripheral membrane protein kinase cdr2p has properties of a dose-dependent ‘sizer’ that controls mitotic entry. As cells grow, the local cdr2p concentration in nodes at the medial cortex accumulates as a measure of cell surface area. Our findings, which challenge a previously proposed pom1p gradient model, lead to a new model in which cells sense their size by using cdr2p to probe the surface area over the whole cell and relay this information to the medial cortex. DOI: http://dx.doi.org/10.7554/eLife.02040.001, eLife digest Although different types of cells come in a variety of shapes and sizes, most cells are able to maintain a fairly consistent size and shape as they grow and divide. For example, the rod-shaped cells of the fission yeast S. pombe grow to be 14 microns long before dividing in the middle to form two new cells. This prevents any single cell becoming too large or small. A similar phenomenon has been observed in other types of cells, so it is clear that cells must be able to measure their own size, and then use that information to trigger cell division. A number of proteins that regulate cell size and cell division in fission yeast have now been identified. These proteins form a pathway in which a protein called pom1p inhibits another protein, cdr2p, which in turn causes a third protein, cdk1p, to start the process of cell division. However, the details of the measurement process and the property that the cells are actually measuring—surface area, volume, mass or something else—remain mysterious. Pan et al. have now used imaging techniques and mathematical modeling to probe the distribution and movements of proteins in fission yeast cells. Their results do not support a previous model in which the cell uses the gradient of pom1p as a ruler to measure cell length. Rather, Pan et al. propose a new model in which the level of cdr2p is used to sense the size of the cell. Individual molecules of cdr2p come together to from clusters called nodes on the cell membrane. As the cell grows larger, more and more cdr2p proteins accumulate in these nodes, which are found in a band around the middle of the cell. When the cells reaches a critical cell size, the increased concentration of cdr2p at these nodes may help to trigger the start of cell division. By examining cells that grow at different rates, Pan et al. show that the rate of accumulation of cdr2p in the nodes depends on how big the cells are, rather than on the length of time that has elapsed. Analysis of fission yeast cells of different shapes shows that cell division starts when the surface area of the cell grows to a certain value, as opposed to starting when the volume or length reach a given value. Pan et al. also show that cdr2p binds to all parts of the cell membrane, not just to the nodes near the middle, and go on to provide a simple mathematical model showing how this property can allow cells to measure their surface area. However, as Pan et al. point out, this is probably just one component of a larger mechanism that tells cells when they need to divide. DOI: http://dx.doi.org/10.7554/eLife.02040.002

Protein synthesis is a regulated cellular process that links nutrients in the environment to organismal growth and development. Here we examine the role of genes that regulate mRNA translation in determining growth, reproduction, stress resistance and lifespan. Translational control of protein synthesis by regulators such as the cap-binding complex and S6 kinase play an important role during growth. We observe that inhibition of various genes in the translation initiation complex including ifg-1, the worm homologue of eIF4G, which is a scaffold protein in the cap-binding complex; and rsks-1, the worm homologue of S6 kinase, results in lifespan extension in Caenorhabditis elegans. Inhibition of ifg-1 or rsks-1 also slows development, reduces fecundity and increases resistance to starvation. A reduction in ifg-1 expression in dauers was also observed, suggesting an inhibition of protein translation during the dauer state. Thus, mRNA translation exerts pleiotropic effects on growth, reproduction, stress resistance and lifespan in C. elegans.

SummaryCells often grow to a certain cell size before entering mitosis and dividing. Two recent articles suggest that fission yeast cells sense their own size through the action of an intracellular gradient emanating from cell tips and a sensor at the cell middle.