How yeast cells measure and control their own size

Many cells, including the unicellular organism budding yeast, control their own size by linking growth and division. Now, a molecular mechanism that allows budding yeast to measure and adjust its own size has been identified.

HFSP Cross-Disciplinary Fellow Kurt Schmoller and HFSP Long-Term Fellow Mardo Kõivomägi and colleagues
authored on Tue, 24 November 2015

Size is a crucial property of cells that not only affects how they can interact with their environment but is also tightly coupled to many intracellular features, such as the size of many organelles. Considering the importance of size for cellular biosynthetic functions, it is not surprising that most cells tightly control their size. Although cells of different species exhibit enormous variation in size (for example, the size of unicellular green algae ranges from about one micrometer to several centimeters), cells of a single species in similar environments show little variation in size. Over several decades, it has become clear that cells control their size by coupling cell division to cell growth. This observation implies that cells can measure their own size. However, the underlying mechanism is still unknown and represents a longstanding and puzzling problem of cell biology. Budding yeast is perfectly suited as a model organism to address this question, because it has long served as a model for the eukaryotic cell cycle, which is responsible for controlling division, and all the key proteins involved are known. Moreover, many features of cell cycle control are conserved from yeast to man.

Figure: Growing budding yeast cells with the cell cycle inhibitor Whi5 labelled with a fluorescent protein.

To determine how growth is coupled to division, we used time-lapse fluorescence microscopy to measure the concentration of the proteins that regulate the cell’s decision to divide in live growing cells. Using this approach, as well as genetic tools and microfluidics to manipulate the concentrations of these proteins, we identified the mechanism that allows yeast cells to sense their own size. We found that cell growth dilutes the cell cycle inhibitor Whi5. In contrast, the concentration of the most upstream activator for cell cycle entry, Cln3, is constant during cell growth. Thus, cell growth shifts the balance between cell cycle activation and inhibition. In addition, after division is triggered, the amount of the inhibitor Whi5 produced during cell division is largely independent of cell size. This results in smaller-born cells starting with a higher Whi5 concentration, which requires them to grow more to sufficiently dilute Whi5 and trigger division.

The cell size independent Whi5 synthesis is in contrast to the general observation that proteins are typically produced in proportion to cell size. Thus, our work demonstrates that cell size-independent synthesis of Whi5 is the fundamental process underlying yeast size control. The simplicity of this mechanism suggests that differential size dependence of protein synthesis might be used as a more general mechanism across species to link distinct cell functions to cell size.

Reference

Dilution of the cell cycle inhibitor Whi5 controls budding-yeast cell size, Schmoller, K.M., Turner, J.J., Kõivomägi, M. and Skotheim J.M., Nature, 526, 268-272 (2015).

Pubmed link