Towards a quantitative and molecular understanding of budding yeast cell size control

• Applicant: Dr. Kurt Michael Schmoller
• Subject Area: Biophysics
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431480687

Size is a key property of cells that has a strong impact on cell growth, determines the cellular amount of proteins and RNA, and is intricately linked to the size of organelles. Accordingly, tight control of cell size is crucial for survival of uni- and multicellular organisms. Across species, rapidly proliferating cell populations achieve size control by a coupling of cell growth and division. Since several decades, extensive efforts were directed towards understanding this coupling, but the underlying molecular mechanisms are still poorly understood. Due to the stochastic nature of cell cycle regulation, a quantitative approach, combining molecular biology, biophysical concepts and mathematical modeling will be necessary to achieve this goal.Unicellular model organisms, in particular budding and fission yeasts, have proven extremely valuable, not only due to their simple geometry, short generation time, and powerful tools available, but also because many aspects of cell cycle control are conserved from yeast to humans. Initially, genetic studies have revealed the regulatory networks involved in yeast cell size control. More recently, the rise of live-cell microscopy provided us with a wealth of single-cell data that resulted in a boost for the field and new phenomenological and mechanistic insights.Budding yeast cell size control occurs mainly at the G1/S transition, which ensures that cells that are born small grow longer during G1. During my postdoctoral work, I have used live-cell microscopy to reveal the underlying size-sensing mechanism. Briefly, I have shown that cell size control is based on the differential synthesis of a cell cycle activator, Cln3, and a cell cycle inhibitor, Whi5, with cell size. Cln3 synthesis increases with cell size, while Whi5 is produced with a size-independent rate. The higher inhibitor-to-activator ratio then ensures that smaller cells grow more before entering the next cell cycle. Importantly, however, this work was constrained to the situation of a constant environment, not accounting for the fact that a major purpose of cell size control is to adjust cell size according to dynamic changes in nutrient conditions.Here, I propose to use a combination of quantitative live-cell microscopy, molecular cell biology, and mathematical modeling, to obtain a quantitative understanding of nutrient-dependent cell size-adaptation. An important step will be to reveal the function of the Whi5 paralog Whi7, and the poorly understood cell cycle regulator Bck2. We will then use a full-cell-cycle modeling framework that we have previously used to explain the steady-state cell size distribution to unravel which cell cycle transitions and cell properties are regulated with changing nutrient conditions. In addition to fundamental insights into budding yeast cell size control, the proposed work will provide general concepts that will be helpful to understand cell size control and adaptation in more complex mammalian cells.

• DFG Programme: Research Grants