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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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Enumeration of green cells in the G1/S transition window.Total number of green (S) cells in the stochastic window as a function of time for the continuous (A), periodic (B) and two-fold periodic (C) models. The blue and green lines with ‘+’ markers indicate two independent simulation datasets corresponding to the upper and lower sequence data from the experiment, respectively.
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pcbi-1003957-g007: Enumeration of green cells in the G1/S transition window.Total number of green (S) cells in the stochastic window as a function of time for the continuous (A), periodic (B) and two-fold periodic (C) models. The blue and green lines with ‘+’ markers indicate two independent simulation datasets corresponding to the upper and lower sequence data from the experiment, respectively.

Mentions: In order to provide credible evidence for the periodicity of the regulatory mode of the G1/S transition in notochordal cells, we enumerated the number of green cells in these three distinct periodic simulation models, as we did in the experimental observation shown in Figure 3C. In each simulation model, we performed two independent simulations, which were assumed to involve the upper and lower columns of notochordal cells. According to the continuous model simulation results, the upper and lower columns of cells did not appear to show any obvious synchronized behavior (Figure 7A). In the simulations with the periodic and the two-fold periodic models (Figure 7B and C), two columns of cells exhibited synchronized oscillation. However, in terms of the stability of oscillation, the two-fold periodicity model was more robust than that of the periodic model. Furthermore, the two-fold periodic model appeared to be most suitable for the experimental model shown in Figure 3C.


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)

Enumeration of green cells in the G1/S transition window.Total number of green (S) cells in the stochastic window as a function of time for the continuous (A), periodic (B) and two-fold periodic (C) models. The blue and green lines with ‘+’ markers indicate two independent simulation datasets corresponding to the upper and lower sequence data from the experiment, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1003957-g007: Enumeration of green cells in the G1/S transition window.Total number of green (S) cells in the stochastic window as a function of time for the continuous (A), periodic (B) and two-fold periodic (C) models. The blue and green lines with ‘+’ markers indicate two independent simulation datasets corresponding to the upper and lower sequence data from the experiment, respectively.
Mentions: In order to provide credible evidence for the periodicity of the regulatory mode of the G1/S transition in notochordal cells, we enumerated the number of green cells in these three distinct periodic simulation models, as we did in the experimental observation shown in Figure 3C. In each simulation model, we performed two independent simulations, which were assumed to involve the upper and lower columns of notochordal cells. According to the continuous model simulation results, the upper and lower columns of cells did not appear to show any obvious synchronized behavior (Figure 7A). In the simulations with the periodic and the two-fold periodic models (Figure 7B and C), two columns of cells exhibited synchronized oscillation. However, in terms of the stability of oscillation, the two-fold periodicity model was more robust than that of the periodic model. Furthermore, the two-fold periodic model appeared to be most suitable for the experimental model shown in Figure 3C.

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