title: Live imaging-based model selection reveals periodic regulation of the stochastic G1/S phase transition in vertebrate axial development.
abstract: In multicellular organism development, a stochastic cellular response is observed, even when a population of cells is exposed to the same environmental conditions. Retrieving the spatiotemporal regulatory mode hidden in the heterogeneous cellular behavior is a challenging task. The G1/S transition observed in cell cycle progression is a highly stochastic process. By taking advantage of a fluorescence cell cycle indicator, Fucci technology, we aimed to unveil a hidden regulatory mode of cell cycle progression in developing zebrafish. Fluorescence live imaging of Cecyil, a zebrafish line genetically expressing Fucci, demonstrated that newly formed notochordal cells from the posterior tip of the embryonic mesoderm exhibited the red (G1) fluorescence signal in the developing notochord. Prior to their initial vacuolation, these cells showed a fluorescence color switch from red to green, indicating G1/S transitions. This G1/S transition did not occur in a synchronous manner, but rather exhibited a stochastic process, since a mixed population of red and green cells was always inserted between newly formed red (G1) notochordal cells and vacuolating green cells. We termed this mixed population of notochordal cells, the G1/S transition window. We first performed quantitative analyses of live imaging data and a numerical estimation of the probability of the G1/S transition, which demonstrated the existence of a posteriorly traveling regulatory wave of the G1/S transition window. To obtain a better understanding of this regulatory mode, we constructed a mathematical model and performed a model selection by comparing the results obtained from the models with those from the experimental data. Our analyses demonstrated that the stochastic G1/S transition window in the notochord travels posteriorly in a periodic fashion, with doubled the periodicity of the neighboring paraxial mesoderm segmentation. This approach may have implications for the characterization of the pathophysiological tissue growth mode.
authors.affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Sugiyama
authors.affiliation: Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Shitsukawa, Toon-city, Ehime, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Saitou
authors.affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kurokawa
authors.affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Sakaue-Sawano
authors.affiliation: Department of Molecular Medicine for Pathogenesis, Graduate School of Medicine, Ehime University, Shitsukawa, Toon-city, Ehime, Japan; Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Shitsukawa, Toon-city, Ehime, Japan; Translational Research Center, Ehime University Hospital, Shitsukawa, Toon-city, Ehime, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Miyawaki
authors.affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan; Division of Bio-Imaging, Proteo-Science Center (PROS), Ehime University, Shitsukawa, Toon-city, Ehime, Japan; Translational Research Center, Ehime University Hospital, Shitsukawa, Toon-city, Ehime, Japan.
authors.forename: Tadahiro
authors.initials: T
authors.lastname: Iimura
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000502:physiology*; D019295:Computational Biology; D003198:Computer Simulation; D004625:Embryo, Nonmammalian / Q000166:cytology*; D047108:Embryonic Development / Q000502:physiology*; D008856:Microscopy, Fluorescence / Q000379:methods; D008954:Models, Biological; D015027:Zebrafish