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Sequential segmentation creates modular body plans of diverse metazoan embryos(1-4). Somitogenesis establishes segmental pattern of vertebrate body axis. A molecular segmentation clock in the presomitic mesoderm (PSM) sets the pace of somite formation(4). However, how cells are primed to form a segment boundary at a specific location remained unknown. Here we developed precise reporters for the clock and double phosphorylated ERK (ppERK) gradient in zebrafish. We discovered that the Her1/7 oscillator drives segmental commitment by periodically lowering ppERK, thus projecting its oscillation on the ppERK gradient. Pulsatile inhibition of the ppERK gradient can fully substitute the role of the clock and kinematic clock waves are dispensable for sequential segmentation. The clock functions upstream of the ppERK, which in turn enables neighboring cells to discretely establish somite boundaries in zebrafish(5). Molecularly divergent clocks and morphogen gradients were identified in sequentially segmenting species(3,4,6-8). Our findings imply versatile clocks may establish sequential segmentation in diverse species as long as they inhibit gradients.

Coordinated spatiotemporal expression of large sets of genes is required for the development and homeostasis of organisms. To achieve this goal, organisms use myriad strategies where they form operons, utilize bidirectional promoters, cluster genes, share enhancers among genes by DNA looping, and form topologically associated domains and transcriptional condensates. Coexpression achieved by these different strategies is hypothesized to have functional importance in minimizing gene expression variability, establishing dosage balance to ensure stoichiometry of protein complexes, and minimizing accumulation of toxic intermediate metabolites. By combining gene-editing tools with computational modeling, recent studies tested the advantages of adjacent genes located in pairs and clusters. We propose that with the advancement of gene editing, single-cell sequencing, and imaging tools, one could readily test the functional importance of different coexpression strategies in a variety of biological processes.