Cell Cycle Heterogeneity Can Generate Robust Cell Type Proportioning

Cell-cell heterogeneity can facilitate lineage choice during embryonic development because it primes cells to respond to differentiation cues. However, remarkably little is known about the origin of heterogeneity or whether intrinsic and extrinsic variation can be controlled to generate reproducible cell type proportioning seen in vivo. Here, we use experimentation and modeling in D. discoideum to demonstrate that population-level cell cycle heterogeneity can be optimized to generate robust cell fate proportioning. First, cell cycle position is quantitatively linked to responsiveness to differentiation-inducing signals. Second, intrinsic variation in cell cycle length ensures cells are randomly distributed throughout the cell cycle at the onset of multicellular development. Finally, extrinsic perturbation of optimal cell cycle heterogeneity is buffered by compensatory changes in global signal responsiveness. These studies thus illustrate key regulatory principles underlying cell-cell heterogeneity optimization and the generation of robust and reproducible fate choice in development. [Display omitted] •Dictyostelium cells break symmetry in a stochastic salt and pepper fashion•Cell cycle position affects responsiveness to differentiation inducing signals•Cell cycle length variation ensures cells are distributed in different cycle phases•Perturbation of cell cycle dynamics is buffered by changes in signal responsiveness Gruenheit et al. find cell cycle position heterogeneity promotes symmetry breaking during development as it helps cells respond to different differentiation cues. Buffering by changes in signal responses ensures this system is robust to perturbation of cell cycle dynamics. This illustrates how heterogeneity can be optimized to facilitate development.