Abstract
Mating of budding yeast cells is a model system for studying cell-cell interactions. Haploid yeast cells secrete mating pheromones that are sensed by the partner which responds by growing a mating projection toward the source. The two projections meet and fuse to form the diploid. Successful mating relies on precise coordination of dynamic extracellular signals, signaling pathways, and cell shape changes in a noisy background. It remains elusive how cells mate accurately and efficiently in a natural multi-cell environment. Here we present the first stochastic model of multiple mating cells whose morphologies are driven by pheromone gradients and intracellular signals. Our novel computational framework encompassed a moving boundary method for modeling both a-cells and α-cells and their cell shape changes, the extracellular diffusion of mating pheromones dynamically coupled with cell polarization, and both external and internal noise. Quantification of mating efficiency was developed and tested for different model parameters. Computer simulations revealed important robustness strategies for mating in the presence of noise. These strategies included the polarized secretion of pheromone, the presence of the α-factor protease Bar1, and the regulation of sensing sensitivity; all were consistent with data in the literature. In addition, we investigated mating discrimination, the ability of an a-cell to distinguish between α-cells either making or not making α-factor, and mating competition, in which multiple a-cells compete to mate with one α-cell. Our simulations were consistent with previous experimental results. Moreover, we performed a combination of simulations and experiments to estimate the diffusion rate of the pheromone a-factor. In summary, we constructed a framework for simulating yeast mating with multiple cells in a noisy environment, and used this framework to reproduce mating behaviors and to identify strategies for robust cell-cell interactions.
Highlights
Cell-to-cell signaling via diffusible molecules is an important mode of communication between cells in many mammalian systems such as neuron axon guidance [1], immune cell recognition [2], and angiogenesis [3]
We found that positioning the secretion and sensing of pheromones at the same location on the cell surface was important
Previous studies focused on the relationship between morphogenesis and its underlying biochemical or mechanical machinery. We extend this concept by including the molecular dynamics within the extracellular space to study multi-cell interactions
Summary
Cell-to-cell signaling via diffusible molecules is an important mode of communication between cells in many mammalian systems such as neuron axon guidance [1], immune cell recognition [2], and angiogenesis [3] These interactions involve sensing an attractant from the partner and responding by moving or growing in the appropriate direction (i.e. chemo-taxis/tropism), while secreting signaling molecules in a reciprocal fashion. By sensing the pheromone molecules (α-factor and a-factor), a- and α-cells detect the presence of a mating partner These secreted peptides form a spatial gradient, bind to the pheromone-specific receptors, and elicit a response that includes cell-cycle arrest, gene expression, and formation of a mating projection (“shmoo”). Snapshots of more simulations are provided in Fig K in S1 Text
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