A Quantitative Study of the Division Cycle of Caulobacter crescentus Stalked Cells

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Abstract
Progression of a cell through the division cycle is tightly controlled at different steps to ensure the integrity of genome replication and partitioning to daughter cells. From published experimental evidence, we propose a molecular mechanism for control of the cell division cycle in Caulobacter crescentus. The mechanism, which is based on the synthesis and degradation of three “master regulator” proteins (CtrA, GcrA, and DnaA), is converted into a quantitative model, in order to study the temporal dynamics of these and other cell cycle proteins. The model accounts for important details of the physiology, biochemistry, and genetics of cell cycle control in stalked C. crescentus cell. It reproduces protein time courses in wild-type cells, mimics correctly the phenotypes of many mutant strains, and predicts the phenotypes of currently uncharacterized mutants. Since many of the proteins involved in regulating the cell cycle of C. crescentus are conserved among many genera of α-proteobacteria, the proposed mechanism may be applicable to other species of importance in agriculture and medicine. The cell cycle is the sequence of events by which a growing cell replicates all its components and divides them more or less evenly between two daughter cells. The timing and spatial organization of these events are controlled by gene–protein interaction networks of great complexity. A challenge for computational biology is to build realistic, accurate, predictive mathematical models of these control systems in a variety of organisms, both eukaryotes and prokaryotes. To this end, we present a model of a portion of the molecular network controlling DNA synthesis, cell cycle–related gene expression, DNA methylation, and cell division in stalked cells of the α-proteobacterium Caulobacter crescentus. The model is formulated in terms of nonlinear ordinary differential equations for the major cell cycle regulatory proteins in Caulobacter: CtrA, GcrA, DnaA, CcrM, and DivK. Kinetic rate constants are estimated, and the model is tested against available experimental observations on wild-type and mutant cells. The model is viewed as a starting point for more comprehensive models of the future that will account, in addition, for the spatial asymmetry of Caulobacter reproduction (swarmer cells as well as stalked cells), the correlation of cell growth and division, and cell cycle checkpoints.