GDI-Mediated Cell Polarization in Yeast Provides Precise Spatial and Temporal Control of Cdc42 Signaling

Cell polarization is a prerequisite for essential processes such as cell migration, proliferation or differentiation. The yeast Saccharomyces cerevisiae under control of the GTPase Cdc42 is able to polarize without the help of cytoskeletal structures and spatial cues through a pathway depending on its guanine nucleotide dissociation inhibitor (GDI) Rdi1. To develop a fundamental understanding of yeast polarization we establish a detailed mechanistic model of GDI-mediated polarization. We show that GDI-mediated polarization provides precise spatial and temporal control of Cdc42 signaling and give experimental evidence for our findings. Cell cycle induced changes of Cdc42 regulation enhance positive feedback loops of active Cdc42 production, and thereby allow simultaneous switch-like regulation of focused polarity and Cdc42 activation. This regulation drives the direct formation of a unique polarity cluster with characteristic narrowing dynamics, as opposed to the previously proposed competition between transient clusters. As the key components of the studied system are conserved among eukaryotes, we expect our findings also to apply to cell polarization in other organisms. Author Summary Cell polarization is a fundamental cellular process that defines a single orientation axis within prokaryotic or eukaryotic cells and is a prerequisite for developmental processes such as cell migration, proliferation or differentiation. In the yeast Saccharomyces cerevisiae cell polarization determines the position of a new growth or bud site. Although many studies have focused on identifying polarity regulators and their interactions, the fundamental mechanisms and features of cell polarity still remain controversial. Here, we develop a detailed mathematical model of diffusion-driven cell polarization, which we verify experimentally. We show that this polarization mechanism provides precise spatial and temporal control of signals, which determine the place of a new growth site. Changes induced by the cell cycle allow simultaneous switch-like regulation of polarization and activation of the GTPase Cdc42, the central polarity regulator which initiates formation of a new bud. This regulation drives direct formation of a unique Cdc42 cluster with characteristic narrowing dynamics and robustly narrow spatial focus. Hence, our analysis reveals fundamental design principles that allow cell polarization to reliably initiate developmental processes at a specific time and place. As the key components of the studied system are conserved among eukaryotes, we expect our findings also to apply to cell polarization in other organisms.