On being the right (cell) size

How cells know when they are the right size Biologists have long recognized that cells exist in a large range of sizes. Cell size is also flexible: Cells can differentiate into another cell type with a very different size. External factors can also influence cell size, but the consistent size of a given cell type shows that cells have mechanisms to measure their own size and adjust their growth rate or rate of cell division to maintain uniformity. Ginzberg et al. review recent advances in understanding how cells know when they are at the right size. Science, this issue 10.1126/science.1245075 BACKGROUND How do the different cell types in our bodies maintain their distinctive and characteristic sizes? Although much is known about the signaling networks that stimulate or suppress cell growth, such as the mammalian target of rapamycin (mTOR) pathway, this central question remains: How do a common set of pathways precisely specify the appropriate size for any given cell type and physiological condition? The precision with which size is controlled is demonstrated by the uniformity in cell size typically seen in tissues. Most epithelial tissues, for example, display a striking regularity in the size and morphology of cells, whereas size heterogeneity can be a sign of neoplastic growth. Most work on the subject of how cell size is regulated has explored the control of cell growth and proliferation by extracellular signals, such as growth factors and cytokines. However, although these signals can dictate the mean size of cells, individual cells will inevitably deviate from that mean. Variability in cell size can arise from variability in growth rate and cell-cycle length or asymmetry in cell division. These sources of variation raise the question of whether they are counteracted by cellular mechanisms that act to increase size homogeneity. Size variation can only be reduced with processes that differentially affect cells of different sizes, despite the fact that they share the same environment. This kind of control requires that individual cells measure their own size and adjust their behavior as necessary to achieve a common target size. ADVANCES In this Review, we present a growing body of evidence that suggests that animal cells autonomously measure and adjust their individual sizes to maintain uniformity within a population. We discuss possible mechanisms by which this can be achieved, including the size-dependent adjustment of cell-cycle length and/or growth rate, as well as the limitations of these strategies. We summarize the progress that has been made thus far in identifying the cell’s size control machinery and highlight important unanswered questions. The presence of mechanisms ensuring precise size specification suggests that there may be an optimal cell size for a particular cell’s function. Here, we address the question of whether cells function most efficiently when at the “right” size by examining cases in which cell size was altered naturally or experimentally. Some tissues seem to easily compensate for cell-size changes, whereas in others, cells appear to perform best at their appropriate size. We highlight examples of cell types, such as pancreatic β cells and adipocytes, in which a relationship between cell size and cell function has been observed. OUTLOOK We conclude by discussing the gaps in our understanding of how cell size is regulated, stressing the questions that have been most neglected. Throughout this Review, we point out the experimental challenges that have hindered progress in this field and emphasize recent technological advances that may allow us to overcome these obstacles. Last, we pose the questions that we anticipate will guide this field in the upcoming years. How is cell size specified? (Left) In populations of proliferating cells, size uniformity may be ensured by linking the processes of growth and cell-cycle progression. One way this can be accomplished is by restricting progress through a particular cell-cycle stage (for example, the G1/S transition) to cells that have reached a specific “target” size. (Right) Typical sizes of various human cell types. Cells are drawn to scale: pancreatic β cells, hepatocytes, keratinocytes, fibroblasts, and adipocytes. ILLUSTRATION CREDIT: K. SUTLIFF/SCIENCE Different animal cell types have distinctive and characteristic sizes. How a particular cell size is specified by differentiation programs and physiology remains one of the fundamental unknowns in cell biology. In this Review, we explore the evidence that individual cells autonomously sense and specify their own size. We discuss possible mechanisms by which size-sensing and size-specification may take place. Last, we explore the physiological implications of size control: Why is it important that particular cell types maintain a particular size? We develop these questions through examination of the current literature and pose the questions that we anticipate will guide this field in the upcoming years.