Understanding mechanisms of cellular geometry scaling

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All life on Earth is made of cells. Intricately organized assemblies of different types of cells make up complex multicellular organisms such as humans or plants. Simpler organisms including yeasts or protozoa live as single cells. Cells come in an astonishing diversity of shapes optimized for their specific function. A cell can grow to different size, depending on the amount of nutrients or other signals in the environment. If specific shape is important, how do cells make sure that it remains the same across different sizes? This is an interesting biological and engineering problem that can be solved by understanding how the intrinsic cellular polarity machinery that generates cell shape by restricting growth to certain sites on the cellular membrane, can decrease or increase the sizes of these growth zones in response to changes in cellular volume. We call this property cellular geometry scaling. It is incredibly widespread in biology but we know very little about it.We will use a simple unicellular fungal organism called Schizosaccharomyces japonicus (S. japonicus) to understand how cells scale their shape. It is a great system for addressing this problem because it grows fast, is easily amenable to genetic manipulations and, of course, exhibits very robust scaling. We previously found that a regulator of the cellular polarity machinery, a protein called Rga4, was critical for scaling. If S. japonicus does not have Rga4, it cannot scale down when nutrients become scarce and dies, demonstrating that the ability to scale is really important. Now we propose to obtain mechanistic explanation for Rga4 function in scaling. Our program will consist of two interrelated objectives. First, we will understand how cellular polarity changes during scaling and how Rga4 contributes to these changes. We will also probe the relationship between Rga4 and a protein called Tea4 that normally functions to landmark growth at specific membrane sites. In the second objective we will investigate how cells regulate Rga4 by phosphorylation to promote scaling when required. Phosphorylation is one of the most important modifications regulating protein function through changes in conformation and we will additionally look at phosphoregulation of many more cellular proteins to reveal hidden connections between different parts of cellular physiology important for scaling.It is essential to do this type of fundamental research in a simple organism because it provides important insights into molecular underpinnings of polarized growth and scaling in all eukaryotic cells, from humans to plants. The answers we get may open entirely new possibilities in dealing with devastating fungal pathogens, which rely on changing their size and shape to infect their hosts.