Coupling of cell proliferation to the segmentation clock ensures robust somite scaling

Abstract

While scaling developmental processes is fundamental to maintaining robust tissue patterning, the mechanisms underlying this process are enigmatic. Somitogenesis, the periodic segmentation of growing mesodermal tissue in vertebrate embryos, involves precise scaling with the unsegmented presomitic mesoderm (PSM) over developmental time and under perturbation. Somitogenesis is spatiotemporally regulated by FGF and Wnt morphogen gradients and the segmentation clock - oscillations in Notch, Wnt, and FGF signalling. Here, we find that cell proliferation is distributed throughout the oscillating PSM. Long-term single-cell tracking in mouse embryo tails uncovered a correlation between cell cycle progression and the segmentation clock, with microfluidics-based entrainment indicating coupling between the cell cycle and signalling oscillations, likely through S-phase inducing Cyclins. A theoretical model suggests this coupling ensures uniform PSM growth, uniform morphogen dilution and precise somite formation, which we validated experimentally by blocking cell proliferation. Our findings reveal that coupling cell proliferation to signalling oscillations is crucial for robust somitogenesis and precise somite scaling.