A Multi-cell, Multi-scale Model of Vertebrate Segmentation and Somite Formation

Hester, Susan D.; Belmonte, Julio M.; Gens, J. Scott; Clendenon, Sherry G.; Glazier, James A.

doi:10.1371/journal.pcbi.1002155

Cited by 118 publications

(139 citation statements)

References 84 publications

(225 reference statements)

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“…We have demonstrated that spatial signals (for instance stemming from a biochemical gradient) can be a direct and (based on the visual and kinematic comparison) effective manner of instructing morphogenesis. This has been shown for various other life forms like Arthropoda and Vertebrata [63], [47], [37]. Our simulations regarding the effectiveness of auxin as the primary signal controlling root growth show that based on local auxin production a stable auxin pattern can be produced, however this potentially a slow process.…”

Section: Discussionsupporting

confidence: 65%

Putting Theory to the Test: Which Regulatory Mechanisms Can Drive Realistic Growth of a Root?

et al. 2014

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In recent years there has been a strong development of computational approaches to mechanistically understand organ growth regulation in plants. In this study, simulation methods were used to explore which regulatory mechanisms can lead to realistic output at the cell and whole organ scale and which other possibilities must be discarded as they result in cellular patterns and kinematic characteristics that are not consistent with experimental observations for the Arabidopsis thaliana primary root. To aid in this analysis, a ‘Uniform Longitudinal Strain Rule’ (ULSR) was formulated as a necessary condition for stable, unidirectional, symplastic growth. Our simulations indicate that symplastic structures are robust to differences in longitudinal strain rates along the growth axis only if these differences are small and short-lived. Whereas simple cell-autonomous regulatory rules based on counters and timers can produce stable growth, it was found that steady developmental zones and smooth transitions in cell lengths are not feasible. By introducing spatial cues into growth regulation, those inadequacies could be avoided and experimental data could be faithfully reproduced. Nevertheless, a root growth model based on previous polar auxin-transport mechanisms violates the proposed ULSR due to the presence of lateral gradients. Models with layer-specific regulation or layer-driven growth offer potential solutions. Alternatively, a model representing the known cross-talk between auxin, as the cell proliferation promoting factor, and cytokinin, as the cell differentiation promoting factor, predicts the effect of hormone-perturbations on meristem size. By down-regulating PIN-mediated transport through the transcription factor SHY2, cytokinin effectively flattens the lateral auxin gradient, at the basal boundary of the division zone, (thereby imposing the ULSR) to signal the exit of proliferation and start of elongation. This model exploration underlines the value of generating virtual root growth kinematics to dissect and understand the mechanisms controlling this biological system.

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Section: Discussionsupporting

confidence: 65%

Putting Theory to the Test: Which Regulatory Mechanisms Can Drive Realistic Growth of a Root?

et al. 2014

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“…Experimental and modeling data have demonstrated that the sweeping wave of segmentation clock oscillations may not even be necessary for proper somite formation (Hester et al, 2010;Soza-Ried et al, 2014). Although initiation of somite patterning may occur in the posterior PSM, additional patterning mechanisms also operate later.…”

Section: Discussionmentioning

confidence: 99%

Dynamics of the slowing segmentation clock reveal alternating two-segment periodicity

et al. 2015

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The formation of reiterated somites along the vertebrate body axis is controlled by the segmentation clock, a molecular oscillator expressed within presomitic mesoderm (PSM) cells. Although PSM cells oscillate autonomously, they coordinate with neighboring cells to generate a sweeping wave of cyclic gene expression through the PSM that has a periodicity equal to that of somite formation. The velocity of each wave slows as it moves anteriorly through the PSM, although the dynamics of clock slowing have not been well characterized. Here, we investigate segmentation clock dynamics in the anterior PSM in developing zebrafish embryos using an in vivo clock reporter, her1:her1-venus. The her1:her1-venus reporter has single-cell resolution, allowing us to follow segmentation clock oscillations in individual cells in real-time. By retrospectively tracking oscillations of future somite boundary cells, we find that clock reporter signal increases in anterior PSM cells and that the periodicity of reporter oscillations slows to about ∼1.5 times the periodicity in posterior PSM cells. This gradual slowing of the clock in the anterior PSM creates peaks of clock expression that are separated at a two-segment periodicity both spatially and temporally, a phenomenon we observe in single cells and in tissue-wide analyses. These results differ from previous predictions that clock oscillations stop or are stabilized in the anterior PSM. Instead, PSM cells oscillate until they incorporate into somites. Our findings suggest that the segmentation clock may signal somite formation using a phase gradient with a two-somite periodicity.

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“…Some promising first results come from an in silico modeling platform: A novel multi-cellular agent-based model (ABMs) of vasculogenesis using the CompuCell3D (http://www.compucell3d.org/) modeling environment supplemented with semi-automatic knowledgebase creation has been developed by ePA. Dynamic cell ABMs have been shown to simulate complex developing systems and, consequently, display a potential to simulate adverse effects (Kleinstreuer et al, 2013;Hester et al, 2011;Shirinifard et al, 2013) and aberrant tissue fusion (Ray and Niswander, 2012).…”

Section: Fig 14: Roadmap To Animal-free Toxicokinetic Predictionsmentioning

confidence: 99%