Cell Sorting and Noise-Induced Cell Plasticity Coordinate to Sharpen Boundaries between Gene Expression Domains

A fundamental question in biology is how sharp boundaries of gene expression form precisely in spite of biological variation/noise. Numerous mechanisms position gene expression domains across fields of cells (e.g. morphogens), but how these domains are refined remains unclear. In some cases, domain boundaries sharpen through differential adhesion-mediated cell sorting. However, boundaries can also sharpen through cellular plasticity, with cell fate changes driven by up- or down-regulation of gene expression. In this context, we have argued that noise in gene expression can help cells transition to the correct fate. Here we investigate the efficacy of cell sorting, gene expression plasticity, and their combination in boundary sharpening using multi-scale, stochastic models. We focus on the formation of hindbrain segments (rhombomeres) in the developing zebrafish as an example, but the mechanisms investigated apply broadly to many tissues. Our results indicate that neither sorting nor plasticity is sufficient on its own to sharpen transition regions between different rhombomeres. Rather the two have complementary strengths and weaknesses, which synergize when combined to sharpen gene expression boundaries.Author Summary: In many developing systems, chemical gradients control the formation of segmental domains of gene expression, specifying distinct domains that go on to form different tissues and structures, in a concentration-dependent manner. These gradients are noisy however, raising the question of how sharply delineated boundaries between distinct segments form. It is crucial that developing systems be able to cope with stochasticity and generate well-defined boundaries between different segmented domains. Previous work suggests that cell sorting and cellular plasticity help sharpen boundaries between segments. However, it remains unclear how effective each of these mechanisms is and what their role in sharpening may be. Motivated by recent experimental observations, we construct a hybrid stochastic model to investigate these questions. We find that neither mechanism is sufficient on its own to sharpen boundaries between different segments. Rather, results indicate each has its own strengths and weaknesses, and that they work together synergistically to promote the development of precise, well defined segment boundaries. Formation of segmented rhombomeres in the zebrafish hindbrain, which later form different components of the central nervous system, is a motivating case for this study.