The John Innes Centre Publications Repository contains details of all publications resulting from our researchers.
The repository also includes Open Access publications, which can be identified by the icons found on search results.
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The creation of this publications repository was funded by BBSRC.
Tissue Dimensionality Influences the Functional Response of Cytotoxic T Lymphocyte-Mediated Killing of Targets.
Frontiers in immunology (7) 668
Publisher's version: 10.3389/fimmu.2016.00668
ID: 55856read more
Cytotoxic T lymphocyte (CTL)-mediated killing of virus infections and tumors occurs over a wide range of conditions. The spatial environments in which CTLs encounter target cells vary from narrow vessels, to two-dimensional epithelial tissues, to densely populated 3-dimensional (3D) T cell areas within lymphoid tissues. How such spatial environments alter the functional response of CTL-mediated killing, i.e., how the killing efficiency depends on cell densities, is unclear. In this study, we perform cellular Potts model simulations in different spatial configurations to investigate how the dimensionality of the space affects the functional response of CTL-mediated killing. Irrespective of the spatial configuration, the function with separate saturation constants for CTL and for target cell densities that we previously proposed can in all cases describe the response, demonstrating its generality. However, the tissue dimensionality determines at which cell densities the killing rate starts to saturate. We show that saturation in a fully 3D environment is stronger than in a "flat" 3D environment, which is largely due to accompanying differences in the CTL-target encounter rates.
eLife (5) 1-43
Publisher's version: 10.7554/eLife.18165
ID: 55268read more
The development of outgrowths from plant shoots depends on formation of epidermal sites of cell polarity convergence with high intracellular auxin at their centre. A parsimonious model for generation of convergence sites is that cell polarity for the auxin transporter PIN1 orients up auxin gradients, as this spontaneously generates convergent alignments. Here we test predictions of this and other models for the patterns of auxin biosynthesis and import. Live imaging of outgrowths from kanadi1 kanadi2 Arabidopsis mutant leaves shows that they arise by formation of PIN1 convergence sites within a proximodistal polarity field. PIN1 polarities are oriented away from regions of high auxin biosynthesis enzyme expression, and towards regions of high auxin importer expression. Both expression patterns are required for normal outgrowth emergence, and may form part of a common module underlying shoot outgrowths. These findings are more consistent with models that spontaneously generate tandem rather than convergent alignments.
Parsimonious Model of Vascular Patterning Links Transverse Hormone Fluxes to Lateral Root Initiation: Auxin Leads the Way, while Cytokinin Levels Out.
PLoS Computational Biology (11) e1004450
Publisher's version: 10.1371/journal.pcbi.1004450
ID: 52019read more
An auxin maximum is positioned along the xylem axis of the Arabidopsis root tip. The pattern depends on mutual feedback between auxin and cytokinins mediated by the PIN class of auxin efflux transporters and AHP6, an inhibitor of cytokinin signalling. This interaction has been proposed to regulate the size and the position of the hormones' respective signalling domains and specify distinct boundaries between them. To understand the dynamics of this regulatory network, we implemented a parsimonious computational model of auxin transport that considers hormonal regulation of the auxin transporters within a spatial context, explicitly taking into account cell shape and polarity and the presence of cell walls. Our analysis reveals that an informative spatial pattern in cytokinin levels generated by diffusion is a theoretically unlikely scenario. Furthermore, our model shows that such a pattern is not required for correct and robust auxin patterning. Instead, auxin-dependent modifications of cytokinin response, rather than variations in cytokinin levels, allow for the necessary feedbacks, which can amplify and stabilise the auxin maximum. Our simulations demonstrate the importance of hormonal regulation of auxin efflux for pattern robustness. While involvement of the PIN proteins in vascular patterning is well established, we predict and experimentally verify a role of AUX1 and LAX1/2 auxin influx transporters in this process. Furthermore, we show that polar localisation of PIN1 generates an auxin flux circuit that not only stabilises the accumulation of auxin within the xylem axis, but also provides a mechanism for auxin to accumulate specifically in the xylem-pole pericycle cells, an important early step in lateral root initiation. The model also revealed that pericycle cells on opposite xylem poles compete for auxin accumulation, consistent with the observation that lateral roots are not initiated opposite to each other.
Plant Physiology (169) 194-208
Publisher's version: 10.1104/pp.15.00343
ID: 53725read more
Upward leaf movement (hyponastic growth) is frequently observed in response to changing environmental conditions and can be induced by the phytohormone ethylene. Hyponasty results from differential growth (i.e. enhanced cell elongation at the proximal abaxial side of the petiole relative to the adaxial side). Here, we characterize Enhanced Hyponasty-d, an activation-tagged Arabidopsis (Arabidopsis thaliana) line with exaggerated hyponasty. This phenotype is associated with overexpression of the mitotic cyclin CYCLINA2;1 (CYCA2;1), which hints at a role for cell divisions in regulating hyponasty. Indeed, mathematical analysis suggested that the observed changes in abaxial cell elongation rates during ethylene treatment should result in a larger hyponastic amplitude than observed, unless a decrease in cell proliferation rate at the proximal abaxial side of the petiole relative to the adaxial side was implemented. Our model predicts that when this differential proliferation mechanism is disrupted by either ectopic overexpression or mutation of CYCA2;1, the hyponastic growth response becomes exaggerated. This is in accordance with experimental observations on CYCA2;1 overexpression lines and cyca2;1 knockouts. We therefore propose a bipartite mechanism controlling leaf movement: ethylene induces longitudinal cell expansion in the abaxial petiole epidermis to induce hyponasty and simultaneously affects its amplitude by controlling cell proliferation through CYCA2;1. Further corroborating the model, we found that ethylene treatment results in transcriptional down-regulation of A2-type CYCLINs and propose that this, and possibly other regulatory mechanisms affecting CYCA2;1, may contribute to this attenuation of hyponastic growth.
The biophysical nature of cells: potential cell behaviours revealed by analytical and computational studies of cell surface mechanics
BMC Biophysics ( )
Publisher's version: 10.1186/s13628-015-0022-x
ID: 49527read more
Background: The biophysical characteristics of cells determinethe shape of individual cells and their packing within tissues. Cellscan form regular or irregular epithelial structures, round up andform clusters, or deform and attach to substrates. The acquired shapeof cells and tissues is a consequence of (i) internal cytoskeletalprocesses, such as actin polymerisation and cortical myosin contraction,(ii) adhesion molecules within the cell membrane that interact withsubstrates and neighbouring cells, and (iii) processes that regulatecell volume. Although these processes seem relatively simple, whencombined they unleash a rich variety of cellular behaviour that isnot readily understandable outside a theoretical framework.Results: Here we present a mathematical and computationalanalysis of a commonly used class of model formalisms that describecell surface mechanics using an energy-based approach. The analyticalstudy reveals the complete possible spectrum of single cell behaviourand tissue packing in both 2D and 3D, by taking the typical core elementsof cell surface mechanics into account: adhesion, cortical tensionand volume conservation. We show that from an energy-based description,forces and tensions can be derived, as well as the prediction of cellbehaviour and tissue packing, providing an intuitive and biologicallyrelevant mapping between modelling parameters and experiments. Thesepredictions are confirmed by the computational outcomes of cell-packinggeometries, both in a vertex-model and in 2D and 3D simulations ofthe Cellular Potts Model.Conclusions: The biological insights and qualitative cellularbehaviours agree with the this analytical study, even across differentmodel formalisms. This illustrates the generality of energy-basedapproaches for cell surface mechanics and highlights how meaningfuland quantitative comparisons between models can be established. Moreover,the mathematical analysis yields direct links between known biophysicalproperties and specific parameter settings within the Cellular PottsModel.
Mathematical Modeling and Experimental Validation of the Spatial Distribution of Boron in the Root of Arabidopsis thaliana Identify High Boron Accumulation in the Tip and Predict a Distinct Root Tip Uptake Function.
Plant Cell Physiology (56) 620-30
Publisher's version: 10.1093/pcp/pcv016
ID: 49410read more
Boron, an essential micronutrient, is transported in roots of Arabidopsis thaliana mainly by two different types of transporters, BORs and NIPs (nodulin26-like intrinsic proteins). Both are plasma membrane localized, but have distinct transport properties and patterns of cell type-specific accumulation with different polar localizations, which are likely to affect boron distribution. Here, we used mathematical modeling and an experimental determination to address boron distributions in the root. A computational model of the root is created at the cellular level, describing the boron transporters as observed experimentally. Boron is allowed to diffuse into roots, in cells and cell walls, and to be transported over plasma membranes, reflecting the properties of the different transporters. The model predicts that a region around the quiescent center has a higher concentration of soluble boron than other portions. To evaluate this prediction experimentally, we determined the boron distribution in roots using laser ablation-inductivity coupled plasma-mass spectrometry. The analysis indicated that the boron concentration is highest near the tip and is lower in the more proximal region of the meristem zone, similar to the pattern of soluble boron distribution predicted by the model. Our model also predicts that upward boron flux does not continuously increase from the root tip toward the mature region, indicating that boron taken up in the root tip is not efficiently transported to shoots. This suggests that root tip-absorbed boron is probably used for local root growth, and that instead it is the more mature root regions which have a greater role in transporting boron toward the shoots.
Biophysical Journal (106) 1780-91
Publisher's version: 10.1016/j.bpj.2014.01.048
ID: 47418read more
Cytotoxic T lymphocytes (CTLs) kill virus-infected cells and tumor cells, and play a critical role in immune protection. Our knowledge of how the CTL killing efficiency varies with CTL and target cell numbers is limited. Here, we simulate a region of lymphoid tissue using a cellular Potts model to characterize the functional response of CTL killing of target cells, and find that the total killing rate saturates both with the CTL and the target cell densities. The relative saturation in CTL and target cell densities is determined by whether a CTL can kill multiple target cells at the same time, and whether a target cell can be killed by many CTLs together. We find that all the studied regimes can be well described by a double-saturation (DS) function with two different saturation constants. We show that this DS model can be mechanistically derived for the cases where target cells are killed by a single CTL. For the other cases, a biological interpretation of the parameters is still possible. Our results imply that this DS function can be used as a tool to predict the cellular interactions in cytotoxicity data.
Journal of Integrative Plant Biology (55) 847-63
Publisher's version: 10.1111/jipb.12092
ID: 47419read more
In the past 20-30 years, developmental biologists have made tremendous progress in identifying genes required for the specification of individual cell types of an organ and in describing how they interact in genetic networks. In comparison, very little is known about the mechanisms that regulate tissue polarity and overall organ patterning. Gynoecia and fruits from members of the Brassicaceae family of flowering plants provide excellent model systems to study organ patterning and tissue specification because they become partitioned into distinct domains whose formation is determined by polarity establishment both at a cellular and whole tissue level. Interactions among key regulators of Arabidopsis gynoecium and fruit development have revealed a network of upstream transcription factor activities required for such tissue differentiation. Regulation of the plant hormone auxin is emerging as both an immediate downstream output and input of these activities, and here we aim to provide an overview of the current knowledge regarding the link between auxin and female reproductive development in plants. In this review, we will also demonstrate how available data can be exploited in a mathematical modeling approach to reveal and understand the feedback regulatory circuits that underpin the polarity establishment, necessary to guide auxin flows.
Development (140) 2061-74
Publisher's version: 10.1242/dev.062984
ID: 41877read more
Tissue-resident memory CD8+ T cells continuously patrol skin epithelia to quickly recognize local antigen.
Proceedings of the National Academy of Sciences of the United States of America (109) 19739-44
Publisher's version: 10.1073/pnas.1208927109
ID: 41340read more
PLoS Computational Biology (8) e1002763
Publisher's version: 10.1371/journal.pcbi.1002763
ID: 41341read more
Bulletin of Mathematical Biology (74) 2570-99
Publisher's version: 10.1007/s11538-012-9766-5
ID: 41342read more
A bistable circuit involving SCARECROW-RETINOBLASTOMA integrates cues to inform asymmetric stem cell division.
Cell (150) 1002-15
Publisher's version: 10.1016/j.cell.2012.07.017
ID: 41339read more
BMC Systems Biology (6) 37
Publisher's version: 10.1186/1752-0509-6-37
ID: 41338read more
How cells integrate complex stimuli: the effect of feedback from phosphoinositides and cell shape on cell polarization and motility.
PLoS Computing Biology (8) e1002402
Publisher's version: 10.1371/journal.pcbi.1002402
ID: 40529read more
Ethylene-induced differential petiole growth in Arabidopsis thaliana involves local microtubule reorientation and cell expansion.
New Phytologist (193) 339-348
Publisher's version: 10.1111/j.1469-8137.2011.03920.x
ID: 40528read more
Nature Reviews Immunology (9) 789-798
Publisher's version: 10.1038/nri2638
ID: 19437read more
Proceedings of the National Academy of Sciences USA (106) 17271-17275
Publisher's version: 10.1073/pnas.0902085106
ID: 19438read more
Journal of Immunological Methods (347) 54-69
Publisher's version: 10.1016/j.jim.2009.05.013
ID: 19439read more
PLoS Biol (6) e307
Publisher's version: 10.1371/journal.pbio.0060307
ID: 19440read more
A quantitative comparison of rates of phagocytosis and digestion of apoptotic cells by macrophages from normal (BALB/c) and diabetes-prone (NOD) mice.
J Appl Physiol (104) 157-169
Publisher's version: 10.1152/japplphysiol.00514.2007
ID: 19441read more
Proc Natl Acad Sci U S A (104) 18549-18554
Publisher's version: 10.1073/pnas.0704235104
ID: 19442read more
Nature (449) 1008-1013
Publisher's version: 10.1038/nature06215
ID: 19443read more
Bull Math Biol (69) 1943-1978
Publisher's version: 10.1007/s11538-007-9200-6
ID: 19445read more
Publisher's version: 10.1007/978-3-7643-8123-3
ID: 19448read more