TIMERR · The role of cell type-specific timing in the robustness of development

Reproducibility in development is maintained via precisely-timed execution of gene regulatory programs required to build all cell types of the embryo. However, many perturbations challenge this robustness and accelerate developmental tempo, leading to increased phenotypic variability. Mechanisms underlying this century-old observation have been obscured by variation inherent to embryogenesis, but advances in statistical single-cell profiling have revealed an unappreciated source of variability: non-uniform progression of development across cell types. Here, I propose to use a combination of ultra-scalable single-cell genomics, cross-species alignment of developmental trajectories, and engineering of developmental rate to understand how cell type-specific timing differences influence reproducibility of development. First, comparing vertebrate species with natural tempo differences, fast-developing zebrafish (Danio rerio) and slow-developing medaka (Oryzias latipes), we aim to generate time-resolved single-cell transcriptomic profiles and map variation in cell type-specific timing. We will relate timing variation to a quantitative robustness measure derived from cell composition profiles for hundreds of embryos, asking how the tempo of development influences its ability to reproducibly build a well-proportioned animal. Second, we aim to identify cell type-specific drivers of timing and coordination. Specifically, we will modulate tempo embryo-wide and test for proportional timing changes across cells by tracking responses to perturbation at the cell type level. We will then use genetic tools to promote lineage-specific acceleration of development, assessing the embryo’s capacity to compensate for an induced asynchrony. In challenging coordinated developmental progression in evolutionary, perturbation, and synthetic contexts, we will resolve how timing impacts reproducibility in development.