Noise-resistant developmental reproducibility in vertebrate somite formation

PLoS Comput Biol. 2019 Feb 4;15(2):e1006579. doi: 10.1371/journal.pcbi.1006579. eCollection 2019 Feb.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Artifacts
  • Body Patterning / physiology*
  • Circadian Rhythm Signaling Peptides and Proteins
  • Developmental Biology / methods
  • Embryo, Mammalian
  • Embryonic Development / physiology*
  • Gene Expression Regulation, Developmental / physiology
  • MAP Kinase Signaling System
  • Mesoderm
  • Models, Molecular
  • Reproducibility of Results
  • Somites / physiology
  • Zebrafish / embryology

Substances

  • Circadian Rhythm Signaling Peptides and Proteins

Grants and funding

This work was partially supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan (to HN, RA, SI, YB, and TM), and the Takeda Science Foundation (to TM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.