scholarly journals Cross-talk between Rho and Rac GTPases drives deterministic exploration of cellular shape space and morphological heterogeneity

Open Biology ◽  
2014 ◽  
Vol 4 (1) ◽  
pp. 130132 ◽  
Author(s):  
Heba Sailem ◽  
Vicky Bousgouni ◽  
Sam Cooper ◽  
Chris Bakal
Keyword(s):  
Cross Talk ◽  
Rho Gtpases ◽  
Cell Biology ◽  
Cell Shape ◽  
Graphical Model ◽  
Shape Space ◽  
Boolean Model ◽  
Complex Nature ◽  
Morphological Heterogeneity ◽  
Cell Shapes

One goal of cell biology is to understand how cells adopt different shapes in response to varying environmental and cellular conditions. Achieving a comprehensive understanding of the relationship between cell shape and environment requires a systems-level understanding of the signalling networks that respond to external cues and regulate the cytoskeleton. Classical biochemical and genetic approaches have identified thousands of individual components that contribute to cell shape, but it remains difficult to predict how cell shape is generated by the activity of these components using bottom-up approaches because of the complex nature of their interactions in space and time. Here, we describe the regulation of cellular shape by signalling systems using a top-down approach. We first exploit the shape diversity generated by systematic RNAi screening and comprehensively define the shape space a migratory cell explores. We suggest a simple Boolean model involving the activation of Rac and Rho GTPases in two compartments to explain the basis for all cell shapes in the dataset. Critically, we also generate a probabilistic graphical model to show how cells explore this space in a deterministic, rather than a stochastic, fashion. We validate the predictions made by our model using live-cell imaging. Our work explains how cross-talk between Rho and Rac can generate different cell shapes, and thus morphological heterogeneity, in genetically identical populations.

scholarly journals An effective model for quantification of cell 3Dshape in early embryogenesis

2021 ◽  
Author(s):  
Zelin Li ◽  
Jianfeng Cao ◽  
Zhongying Zhao ◽  
Hong Yan
Keyword(s):  
Cell Fate ◽  
Cell Shape ◽  
Developmental Process ◽  
Morphological Changes ◽  
Shape Space ◽  
Effective Model ◽  
Cell Stage ◽  
Cell Shapes ◽  
Dimensional Shape ◽  
Low Dimensional

Abstract Background: The developmental process is featured by fabulous morphogenesis in multicellular organisms. Describing morphological changes quantitatively concretes the way to investigating both intra and inter cell regulations on cell fate. While Caenorhabditis elegans has been used as a model for cell and development studies for a long time, the exploration of how cell shape is precisely controlled keeps obscured by the lack of methods to model morphological features. Currently, in order to characterize the features of cell shape involved in cell migration and differentiation, there is an increasing demand in analyzing cell shape systematically, especially when many works have contributed to cell reconstruction. Results: In this work, Spherical harmonics and Principal component analysis integrated Cell Shape quantification Models (SPCSMs) is proposed to represent cell shapes in a low-dimensional shape space. SPCSMs incorporates a complete pipeline to quantify cell shapes and analyze their morphological phenotypes in three dimensional (3D) reconstructions. Based on the framework, we extract biological patterns in the lineage of C. elegans embryo before 350-cell stage, during which all hypodermis cells deformed like a funnel and can be recognized by this shape pattern. Finally, SPCSMs is compared with two cell shape representation methods, which substantiates the effectiveness and robustness of our method. Conclusion: SPCSMs provides a general method to decribe shapes in low-dimensional shape space with compact parameters. It can quantify the shapes of cells from single-cell resolution images obtained over one-minute intervals, making it possible for the recognition of developmental patterns in cell lineages. SPCSMs is expected to be an effective model for biologists to explore the relationships between the shapes of cells and their fates.

scholarly journals Joint modeling of cell and nuclear shape variation

2015 ◽  
Vol 26 (22) ◽  
pp. 4046-4056 ◽  
Author(s):  
Gregory R. Johnson ◽  
Taraz E. Buck ◽  
Devin P. Sullivan ◽  
Gustavo K. Rohde ◽  
Robert F. Murphy
Keyword(s):  
Cell Biology ◽  
Cell Shape ◽  
Computational Cost ◽  
Three Dimensional ◽  
Joint Modeling ◽  
Shape Space ◽  
Nuclear Shape ◽  
Shape Variation ◽  
Shape Spaces ◽  
Low Dimensional

Modeling cell shape variation is critical to our understanding of cell biology. Previous work has demonstrated the utility of nonrigid image registration methods for the construction of nonparametric nuclear shape models in which pairwise deformation distances are measured between all shapes and are embedded into a low-dimensional shape space. Using these methods, we explore the relationship between cell shape and nuclear shape. We find that these are frequently dependent on each other and use this as the motivation for the development of combined cell and nuclear shape space models, extending nonparametric cell representations to multiple-component three-dimensional cellular shapes and identifying modes of joint shape variation. We learn a first-order dynamics model to predict cell and nuclear shapes, given shapes at a previous time point. We use this to determine the effects of endogenous protein tags or drugs on the shape dynamics of cell lines and show that tagged C1QBP reduces the correlation between cell and nuclear shape. To reduce the computational cost of learning these models, we demonstrate the ability to reconstruct shape spaces using a fraction of computed pairwise distances. The open-source tools provide a powerful basis for future studies of the molecular basis of cell organization.

scholarly journals Modeling cell shape diversity arising from complex Rho GTPase dynamics

2019 ◽  
Author(s):  
Cole Zmurchok ◽  
William R. Holmes
Keyword(s):  
Rho Gtpases ◽  
Cell Shape ◽  
Rho Gtpase ◽  
Regulatory System ◽  
Activity Levels ◽  
Imaging Studies ◽  
Individual Parameter ◽  
The Core ◽  
Signaling Dynamics ◽  
Cell Shapes

ABSTRACTIt is well known that cells exhibit a variety of morphologically distinct responses to their environments that manifest in their cell shape. Some protrude uniformly to increase substrate contacts, others are broadly contrac-tile, some polarize to facilitate migration, and yet others exhibit mixtures of these responses. Prior imaging studies have identified a discrete collection of shapes that the majority of cells display and have demonstrated links between those shapes and activity levels of the cytoskeletal regulators Rho GTPases. Here we use a novel computational modeling approach to demonstrate that well known Rho GTPase signaling dynamics naturally give rise to this diverse but discrete (rather than continuum) set of morphologies. Specifically, the combination of auto-activation and mutually-antagonistic crosstalk between GTPases along with the conservative membrane (un)binding dynamics readily explain at least 6 of the 7 commonly observed morphologies. We further use this methodology to map the entire parameter space of this model and show that in appropriate regimes, individual parameter sets give rise to a variety of different morphologies. This provides an explanation for how seemingly similar cells of the same fate derived from the same population can exhibit a diverse array of cell shapes in imaging studies. These results thus demonstrate that Rho GTPases form the core of a cytoskeletal regulatory system governing cell shape, further supporting the picture that they act as a central signaling hub determining how cells respond to their environmental context.

scholarly journals PAK and other Rho-associated kinases – effectors with surprisingly diverse mechanisms of regulation

2005 ◽  
Vol 386 (2) ◽  
pp. 201-214 ◽  
Author(s):  
Zhou-shen ZHAO ◽  
Ed MANSER
Keyword(s):  
Rho Gtpases ◽  
Cell Biology ◽  
Rho Gtpase ◽  
Rho Kinase ◽  
Molecular Switches ◽  
Eukaryotic Cell ◽  
Effector Proteins ◽  
Downstream Effector ◽  
P21 Activated Kinase ◽  
Do So

The Rho GTPases are a family of molecular switches that are critical regulators of signal transduction pathways in eukaryotic cells. They are known principally for their role in regulating the cytoskeleton, and do so by recruiting a variety of downstream effector proteins. Kinases form an important class of Rho effector, and part of the biological complexity brought about by switching on a single GTPase results from downstream phosphorylation cascades. Here we focus on our current understanding of the way in which different Rho-associated serine/threonine kinases, denoted PAK (p21-activated kinase), MLK (mixed-lineage kinase), ROK (Rho-kinase), MRCK (myotonin-related Cdc42-binding kinase), CRIK (citron kinase) and PKN (protein kinase novel), interact with and are regulated by their partner GTPases. All of these kinases have in common an ability to dimerize, and in most cases interact with a variety of other proteins that are important for their function. A diversity of known structures underpin the Rho GTPase–kinase interaction, but only in the case of PAK do we have a good molecular understanding of kinase regulation. The ability of Rho GTPases to co-ordinate spatial and temporal phosphorylation events explains in part their prominent role in eukaryotic cell biology.

scholarly journals Feedback Microtubule Control and Microtubule-Actin Cross-talk inArabidopsisRevealed by Integrative Proteomic and Cell Biology Analysis ofKATANIN 1Mutants

2017 ◽  
Vol 16 (9) ◽  
pp. 1591-1609 ◽  
Author(s):  
Tomáš Takáč ◽  
Olga Šamajová ◽  
Tibor Pechan ◽  
Ivan Luptovčiak ◽  
Jozef Šamaj
Keyword(s):  
Cross Talk ◽  
Cell Biology

scholarly journals Apolar and polar transitions drive the conversion between amoeboid and mesenchymal shapes in melanoma cells

2015 ◽  
Vol 26 (22) ◽  
pp. 4163-4170 ◽  
Author(s):  
Sam Cooper ◽  
Amine Sadok ◽  
Vicky Bousgouni ◽  
Chris Bakal
Keyword(s):  
Quantitative Imaging ◽  
Three Dimensional ◽  
Shape Space ◽  
Melanoma Cells ◽  
Collagen Matrices ◽  
Morphological Heterogeneity ◽  
Rho Family Gtpases ◽  
Metastatic Process ◽  
Rho Family ◽  
Single Living

Melanoma cells can adopt two functionally distinct forms, amoeboid and mesenchymal, which facilitates their ability to invade and colonize diverse environments during the metastatic process. Using quantitative imaging of single living tumor cells invading three-dimensional collagen matrices, in tandem with unsupervised computational analysis, we found that melanoma cells can switch between amoeboid and mesenchymal forms via two different routes in shape space—an apolar and polar route. We show that whereas particular Rho-family GTPases are required for the morphogenesis of amoeboid and mesenchymal forms, others are required for transitions via the apolar or polar route and not amoeboid or mesenchymal morphogenesis per se. Altering the transition rates between particular routes by depleting Rho-family GTPases can change the morphological heterogeneity of cell populations. The apolar and polar routes may have evolved in order to facilitate conversion between amoeboid and mesenchymal forms, as cells are either searching for, or attracted to, particular migratory cues, respectively.

Small Rho GTPases in the control of cell shape and mobility

2013 ◽  
Vol 71 (9) ◽  
pp. 1703-1721 ◽  
Author(s):  
Arun Murali ◽  
Krishnaraj Rajalingam
Keyword(s):  
Rho Gtpases ◽  
Cell Shape ◽  
Small Rho Gtpases

Regulation of cell shape in Euglena gracilis. III. Involvement of stable microtubules

1985 ◽  
Vol 74 (1) ◽  
pp. 219-237
Author(s):  
C.L. Lachney ◽  
T.A. Lonergan
Keyword(s):  
Euglena Gracilis ◽  
Cell Shape ◽  
Microtubule Assembly ◽  
Live Cells ◽  
Microtubule Depolymerization ◽  
Cytoplasmic Microtubule ◽  
Intact Cells ◽  
Calmodulin Antagonist ◽  
Cell Shapes ◽  
In Cells

The role of cytoplasmic microtubules in a recently reported biological clock-controlled rhythm in cell shape of the alga Euglena gracilis (strain Z) was examined using indirect immunofluorescence microscopy. The resulting fluorescent patterns indicated that, unlike many other cell systems, Euglena cells apparently change from round to long to round cell shape without associated cytoplasmic microtubule assembly and disassembly. Instead, the different cell shapes were correlated with microtubule patterns, which suggested that movement of stable microtubules to accomplish cell shape changes. In live intact cells, these microtubules were demonstrated by immunofluorescence to be stable to lowered temperature and elevated intracellular Ca2+ levels, treatments that are commonly used to depolymerize microtubules. In cells extracted in detergent at low temperature or in the presence of elevated Ca2+ levels, the fluorescent image of the microtubules was disrupted. Transmission electron microscopy confirmed the loss of one subset of pellicle microtubules. The difference in microtubule stability to these agents between live intact cells and cells extracted in detergent suggested the presence of a microtubule-stabilizing factor in live cells, which is released from the cell by extraction with detergent, thereby permitting microtubule depolymerization by Ca2+ or lowered temperature. The calmodulin antagonist trifluoperazine prevented the Ca2+-induced disruption of the fluorescent microtubule pattern in cells extracted in detergent. These results implied the involvement of calmodulin in the sensitivity to Ca2+ of the microtubules of cells extracted in detergent.

Abstract 524: Identification of Roles for the Rho-Specific Guanine Nucleotide Dissociation Inhibitor (RhoGDI) Ly-Gdi in Platelet Function

2017 ◽  
Vol 37 (suppl_1) ◽  
Author(s):  
Anh T Ngo ◽  
Marisa L Thierheimer ◽  
Özgün Babur ◽  
Anne D Rocheleau ◽  
Xiaolin Nan ◽  
...  
Keyword(s):  
Platelet Function ◽  
Rho Gtpases ◽  
Cell Biology ◽  
Rho Gtpase ◽  
Thrombus Formation ◽  
Super Resolution ◽  
Dependent Manner ◽  
Guanine Nucleotide ◽  
Morphological Alterations ◽  
Guanine Nucleotide Dissociation Inhibitor

Introduction: Upon activation, platelets undergo specific morphological alterations critical to hemostatic plug and thrombus formation via actin cytoskeletal reorganizations driven by the Rho GTPases Rac1, Cdc42 and RhoA. Here we investigate roles for Rho-specific guanine nucleotide dissociation inhibitor proteins (RhoGDIs) in regulating platelet function. Methods and Hypothesis: Through an approach combining pharmacology, cell biology and systems biology methods we assessed the hypothesis that RhoGDI proteins regulate Rho GTPase-driven platelet functions downstream of platelet integrin and glycoprotein receptors. Results: We find that platelets express two RhoGDI family members, RhoGDI and Ly-GDI. Antibody interference and platelet spreading experiments suggest a specific role for Ly-GDI in platelet function. Intracellular staining and super resolution microscopy assays find that Ly-GDI displays an asymmetric, polarized localization that largely overlaps with Rac1 and Cdc42 as well as microtubules and protein kinase C (PKC) in platelets adherent to fibrinogen. Signaling studies based on interactome and pathways analyses also support a regulatory role for Ly-GDI in platelets, as Ly-GDI is phosphorylated at PKC substrate motifs in a PKC-dependent manner in response to the platelet collagen receptor glycoprotein (GP)VI-specific agonist collagen-related peptide. Notably, inhibition of PKC diffuses the polarized organization of Ly-GDI in spread platelets relative to its colocalization with Rac1 and Cdc42. Conclusion: In conclusion, our results support roles for Ly-GDI as a localized regulator of Rho GTPases in platelets and link PKC and Rho GTPase signaling systems to platelet function.

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