Abstract
The reproducibility of embryonic development is remarkable, although molecular processes are intrinsically stochastic at the single-cell level. How the multicellular system resists the inevitable noise to acquire developmental reproducibility constitutes a fundamental question in developmental biology. Toward this end, we focused on vertebrate somitogenesis as a representative system, because somites are repeatedly reproduced within a single embryo whereas such reproducibility is lost in segmentation clock gene-deficient embryos. However, the effect of noise on developmental reproducibility has not been fully investigated, because of the technical difficulty in manipulating the noise intensity in experiments. In this study, we developed a computational model of ERK-mediated somitogenesis, in which bistable ERK activity is regulated by an FGF gradient, cell-cell communication, and the segmentation clock, subject to the intrinsic noise. The model simulation generated our previous in vivo observation that the ERK activity was distributed in a step-like gradient in the presomitic mesoderm, and its boundary was posteriorly shifted by the clock in a stepwise manner, leading to regular somite formation. Here, we showed that this somite regularity was robustly maintained against the noise. Removing the clock from the model predicted that the stepwise shift of the ERK activity occurs at irregular timing with irregular distance owing to the noise, resulting in somite size variation. This model prediction was recently confirmed by live imaging of ERK activity in zebrafish embryos. Through theoretical analysis, we presented a mechanism by which the clock reduces the inherent somite irregularity observed in clock-deficient embryos. Therefore, this study indicates a novel role of the segmentation clock in noise-resistant developmental reproducibility.
Highlights
Embryonic development in multicellular organisms is highly reproducible
The segmentation clock has been widely considered vital for somite formation, because clock-deficient embryos display severe segmental defects
Irregular somites are still formed, suggesting that the clock is not required for somite formation itself but rather endows it with developmental reproducibility
Summary
Embryonic development in multicellular organisms is highly reproducible. Biochemical reactions at the single-cell level are intrinsically stochastic owing to the low copy numbers of expressed molecules [1,2,3]. It is believed that organisms have a homeostatic mechanism that can resist the stochasticity of cells, while maintaining the precision and reproducibility required for normal development [4]. How the noise affects development in vivo remains unclear, because of the technical difficulty in manipulating the noise intensity in experiments. We approached this issue through computational modeling, especially focusing on vertebrate somitogenesis as a model biological system. Equal-sized somites are continuously produced within a single embryo (Fig 1A and 1B); reproducibility can be evaluated in vertebrate somitogenesis within single, rather than among different, embryos
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