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Live imaging-based model selection reveals periodic regulation of the stochastic G1/S phase transition in vertebrate axial development.

Sugiyama M, Saitou T, Kurokawa H, Sakaue-Sawano A, Imamura T, Miyawaki A, Iimura T - PLoS Comput. Biol. (2014)

Bottom Line: 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.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.This approach may have implications for the characterization of the pathophysiological tissue growth mode.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.

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.

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In silico simulation reproduces noisy cell cycle progression.(A and B) Two-dimensional map of simulated cell cycle progression on the plane of time and space (anterior-posterior axis). Simulations of the continuous model (z = 1) and periodic model (z = 8) were implemented. (C) Total number of cells in the G1 and S phases as a function of time, respectively. The green and red lines, and the dark-green and orange lines denote the simulation results obtained by the continuous model and the periodic model, respectively. (D) Positions of the ARC (red line) and PGC (green line) as a function of time, respectively. The results obtained by the continuous and periodic models were drawn individually.
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pcbi-1003957-g005: In silico simulation reproduces noisy cell cycle progression.(A and B) Two-dimensional map of simulated cell cycle progression on the plane of time and space (anterior-posterior axis). Simulations of the continuous model (z = 1) and periodic model (z = 8) were implemented. (C) Total number of cells in the G1 and S phases as a function of time, respectively. The green and red lines, and the dark-green and orange lines denote the simulation results obtained by the continuous model and the periodic model, respectively. (D) Positions of the ARC (red line) and PGC (green line) as a function of time, respectively. The results obtained by the continuous and periodic models were drawn individually.

Mentions: With this parameter setting of G1/S transition probability, the stochastic modes of the G1/S progression were seen in both the continuous and periodic models (Figures 5A and 5B, Movie S3 and S4). Quantification of the temporal changes in the total number of green cells under the continuous (z = 1) and periodic (z = 8) modes did not show any obvious distinction due to the stochasticity (Figure 5C), as observed in the experimental data analyses shown in Figure 2C.


Live imaging-based model selection reveals periodic regulation of the stochastic G1/S phase transition in vertebrate axial development.

Sugiyama M, Saitou T, Kurokawa H, Sakaue-Sawano A, Imamura T, Miyawaki A, Iimura T - PLoS Comput. Biol. (2014)

In silico simulation reproduces noisy cell cycle progression.(A and B) Two-dimensional map of simulated cell cycle progression on the plane of time and space (anterior-posterior axis). Simulations of the continuous model (z = 1) and periodic model (z = 8) were implemented. (C) Total number of cells in the G1 and S phases as a function of time, respectively. The green and red lines, and the dark-green and orange lines denote the simulation results obtained by the continuous model and the periodic model, respectively. (D) Positions of the ARC (red line) and PGC (green line) as a function of time, respectively. The results obtained by the continuous and periodic models were drawn individually.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4256085&req=5

pcbi-1003957-g005: In silico simulation reproduces noisy cell cycle progression.(A and B) Two-dimensional map of simulated cell cycle progression on the plane of time and space (anterior-posterior axis). Simulations of the continuous model (z = 1) and periodic model (z = 8) were implemented. (C) Total number of cells in the G1 and S phases as a function of time, respectively. The green and red lines, and the dark-green and orange lines denote the simulation results obtained by the continuous model and the periodic model, respectively. (D) Positions of the ARC (red line) and PGC (green line) as a function of time, respectively. The results obtained by the continuous and periodic models were drawn individually.
Mentions: With this parameter setting of G1/S transition probability, the stochastic modes of the G1/S progression were seen in both the continuous and periodic models (Figures 5A and 5B, Movie S3 and S4). Quantification of the temporal changes in the total number of green cells under the continuous (z = 1) and periodic (z = 8) modes did not show any obvious distinction due to the stochasticity (Figure 5C), as observed in the experimental data analyses shown in Figure 2C.

Bottom Line: 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.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.This approach may have implications for the characterization of the pathophysiological tissue growth mode.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Cell Function and Dynamics, Advanced Technology Development Group, Brain Science Institute, RIKEN, Wako-city, Saitama, Japan.

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.

Show MeSH
Related in: MedlinePlus