A Comparison of Mathematical Models for Polarization of Single Eukaryotic Cells in Response to Guided Cues

Polarization, a primary step in the response of an individual eukaryotic cell to a spatial stimulus, has attracted numerous theoretical treatments complementing experimental studies in a variety of cell types. While the phenomenon itself is universal, details differ across cell types, and across classes of models that have been proposed. Most models address how symmetry breaking leads to polarization, some in abstract settings, others based on specific biochemistry. Here, we compare polarization in response to a stimulus (e.g., a chemoattractant) in cells typically used in experiments (yeast, amoebae, leukocytes, keratocytes, fibroblasts, and neurons), and, in parallel, responses of several prototypical models to typical stimulation protocols. We find that the diversity of cell behaviors is reflected by a diversity of models, and that some, but not all models, can account for amplification of stimulus, maintenance of polarity, adaptation, sensitivity to new signals, and robustness.

[1]  Timothy J. Mitchison,et al.  Spatial control of actin polymerization during neutrophil chemotaxis , 1999, Nature Cell Biology.

[2]  Lani Wu,et al.  Spontaneous Cell Polarization Through Actomyosin-Based Delivery of the Cdc42 GTPase , 2003, Science.

[3]  J Krishnan,et al.  Analysis of the signal transduction properties of a module of spatial sensing in eukaryotic chemotaxis , 2003, Bulletin of mathematical biology.

[4]  H. Levine,et al.  Transient localized patterns in noise-driven reaction-diffusion systems. , 2010, Physical review letters.

[5]  Marc W. Kirschner,et al.  A PtdInsP3- and Rho GTPase-mediated positive feedback loop regulates neutrophil polarity , 2002, Nature Cell Biology.

[6]  Liang Li,et al.  Persistent Cell Motion in the Absence of External Signals: A Search Strategy for Eukaryotic Cells , 2008, PloS one.

[7]  J Krishnan,et al.  A modeling framework describing the enzyme regulation of membrane lipids underlying gradient perception in Dictyostelium cells. , 2004, Journal of theoretical biology.

[8]  M. Ueda,et al.  Stochastic signal processing and transduction in chemotactic response of eukaryotic cells. , 2007, Biophysical journal.

[9]  Anna Huttenlocher,et al.  Differential regulation of protrusion and polarity by PI3K during neutrophil motility in live zebrafish. , 2010, Developmental cell.

[10]  Shu Chien,et al.  Effects of cell tension on the small GTPase Rac , 2002, The Journal of cell biology.

[11]  J Krishnan,et al.  Receptor-mediated and intrinsic polarization and their interaction in chemotaxing cells. , 2007, Biophysical journal.

[12]  Eugenio Marco,et al.  Endocytosis Optimizes the Dynamic Localization of Membrane Proteins that Regulate Cortical Polarity , 2007, Cell.

[13]  Brian D. Slaughter,et al.  Dual modes of cdc42 recycling fine-tune polarized morphogenesis. , 2009, Developmental cell.

[14]  Boris N Kholodenko,et al.  Long-range signaling by phosphoprotein waves arising from bistability in protein kinase cascades , 2006, Molecular systems biology.

[15]  P. Iglesias,et al.  Two complementary, local excitation, global inhibition mechanisms acting in parallel can explain the chemoattractant-induced regulation of PI(3,4,5)P3 response in dictyostelium cells. , 2004, Biophysical journal.

[16]  A. Coniglio,et al.  Diffusion-limited phase separation in eukaryotic chemotaxis. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Martin Meier-Schellersheim,et al.  Locally controlled inhibitory mechanisms are involved in eukaryotic GPCR-mediated chemosensing , 2007, The Journal of cell biology.

[18]  Shuji Ishihara,et al.  A Mass Conserved Reaction–Diffusion System Captures Properties of Cell Polarity , 2006, PLoS Comput. Biol..

[19]  Christopher V. Rao,et al.  A Mathematical Model for Neutrophil Gradient Sensing and Polarization , 2007, PLoS Comput. Biol..

[20]  Lewis C. Cantley,et al.  The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function* , 1999, The Journal of Biological Chemistry.

[21]  A. Narang Spontaneous polarization in eukaryotic gradient sensing: a mathematical model based on mutual inhibition of frontness and backness pathways. , 2005, Journal of theoretical biology.

[22]  P. V. van Haastert,et al.  Uniform cAMP stimulation of Dictyostelium cells induces localized patches of signal transduction and pseudopodia. , 2003, Molecular biology of the cell.

[23]  Leah Edelstein-Keshet,et al.  Phosphoinositides and Rho proteins spatially regulate actin polymerization to initiate and maintain directed movement in a 1 D model of a motile cell , 2006 .

[24]  Erik S. Welf,et al.  Signaling pathways that control cell migration: models and analysis , 2011, Wiley interdisciplinary reviews. Systems biology and medicine.

[25]  Alexandra Jilkine,et al.  Wave-pinning and cell polarity from a bistable reaction-diffusion system. , 2008, Biophysical journal.

[26]  D. Lauffenburger,et al.  Self-organization of polarized cell signaling via autocrine circuits: computational model analysis. , 2004, Biophysical journal.

[27]  P. V. van Haastert,et al.  A diffusion-translocation model for gradient sensing by chemotactic cells. , 2001, Biophysical journal.

[28]  Betty J Gaffney Anesthesia, analgesia, and euphoria. , 2007, Biophysical journal.

[29]  Atul Narang,et al.  A mechanistic model for eukaryotic gradient sensing: spontaneous and induced phosphoinositide polarization. , 2004, Journal of theoretical biology.

[30]  W. Rappel,et al.  Directional sensing in eukaryotic chemotaxis: a balanced inactivation model. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[31]  G Ortenzi,et al.  Patch coalescence as a mechanism for eukaryotic directional sensing. , 2007, Physical review letters.

[32]  Indrani Bose,et al.  Singularity in Polarization: Rewiring Yeast Cells to Make Two Buds , 2009, Cell.

[33]  Robert H. Insall,et al.  Understanding eukaryotic chemotaxis: a pseudopod-centred view , 2010, Nature Reviews Molecular Cell Biology.

[34]  Till Bretschneider,et al.  Reversal of cell polarity and actin-myosin cytoskeleton reorganization under mechanical and chemical stimulation. , 2008, Biophysical journal.

[35]  Jason M Haugh,et al.  Spatial analysis of 3' phosphoinositide signaling in living fibroblasts: I. Uniform stimulation model and bounds on dimensionless groups. , 2004, Biophysical journal.

[36]  Pablo A Iglesias,et al.  Cells navigate with a local-excitation, global-inhibition-biased excitable network , 2010, Proceedings of the National Academy of Sciences.

[37]  Andrew B Goryachev,et al.  Dynamics of Cdc42 network embodies a Turing‐type mechanism of yeast cell polarity , 2008, FEBS letters.

[38]  A. Levchenko,et al.  Models of eukaryotic gradient sensing: application to chemotaxis of amoebae and neutrophils. , 2001, Biophysical journal.

[39]  D. Lauffenburger,et al.  A Mathematical Model for Chemoattractant Gradient Sensing Based on Receptor-Regulated Membrane Phospholipid Signaling Dynamics , 2001, Annals of Biomedical Engineering.

[40]  Katherine C. Chen,et al.  Sniffers, buzzers, toggles and blinkers: dynamics of regulatory and signaling pathways in the cell. , 2003, Current opinion in cell biology.

[41]  H. Meinhardt Orientation of chemotactic cells and growth cones: models and mechanisms. , 1999, Journal of cell science.

[42]  A. Hall,et al.  Cell migration: Rho GTPases lead the way. , 2004, Developmental biology.

[43]  Till Bretschneider,et al.  The three-dimensional dynamics of actin waves, a model of cytoskeletal self-organization. , 2009, Biophysical journal.

[44]  Miki Y. Matsuo,et al.  Ordered Patterns of Cell Shape and Orientational Correlation during Spontaneous Cell Migration , 2008, PloS one.

[45]  P. V. van Haastert,et al.  The Ordered Extension of Pseudopodia by Amoeboid Cells in the Absence of External Cues , 2009, PloS one.

[46]  Alexandra Jilkine,et al.  Polarization and Movement of Keratocytes: A Multiscale Modelling Approach , 2006, Bulletin of mathematical biology.

[47]  T. Meyer,et al.  A local coupling model and compass parameter for eukaryotic chemotaxis. , 2005, Developmental cell.

[48]  W. Rappel,et al.  External and internal constraints on eukaryotic chemotaxis , 2010, Proceedings of the National Academy of Sciences.

[49]  C. V. Rao,et al.  Calling heads from tails: the role of mathematical modeling in understanding cell polarization. , 2009, Current opinion in cell biology.

[50]  Paola Causin,et al.  Autocatalytic Loop, Amplification and Diffusion: A Mathematical and Computational Model of Cell Polarization in Neural Chemotaxis , 2009, PLoS Comput. Biol..

[51]  A. Noegel,et al.  The Dictyostelium discoideum family of Rho-related proteins. , 2001, Nucleic acids research.

[52]  Natalie Andrew,et al.  Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions , 2007, Nature Cell Biology.

[53]  Jason M Haugh,et al.  Spatial analysis of 3' phosphoinositide signaling in living fibroblasts, III: influence of cell morphology and morphological Polarity. , 2005, Biophysical journal.

[54]  J W Sedat,et al.  Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis. , 1999, Molecular biology of the cell.

[55]  T. Yanagida,et al.  Self-organization of the phosphatidylinositol lipids signaling system for random cell migration , 2010, Proceedings of the National Academy of Sciences.

[56]  F. J. Martini,et al.  Migration of cortical interneurons relies on branched leading process dynamics , 2009, Cell adhesion & migration.

[57]  Richard A. Firtel,et al.  Rap1 controls cell adhesion and cell motility through the regulation of myosin II , 2007, The Journal of cell biology.

[58]  Alexander van Oudenaarden,et al.  A system of counteracting feedback loops regulates Cdc42p activity during spontaneous cell polarization. , 2005, Developmental cell.

[59]  R. Kay,et al.  Chemotaxis in the Absence of PIP3 Gradients , 2007, Current Biology.

[60]  Tian Jin,et al.  Key Role of Local Regulation in Chemosensing Revealed by a New Molecular Interaction-Based Modeling Method , 2006, PLoS Comput. Biol..

[61]  Rong Li,et al.  Spontaneous cell polarization: undermining determinism , 2003, Nature Cell Biology.

[62]  Pablo A. Iglesias,et al.  Modeling the Cell's Guidance System , 2002, Science's STKE.

[63]  M. G. Vicker,et al.  The locomotion, shape and pseudopodial dynamics of unstimulated Dictyostelium cells are not random. , 1993, Journal of cell science.

[64]  H. Meinhardt,et al.  Applications of a theory of biological pattern formation based on lateral inhibition. , 1974, Journal of cell science.

[65]  J. Ferrell Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. , 2002, Current opinion in cell biology.

[66]  P. Devreotes,et al.  Eukaryotic Chemotaxis: Distinctions between Directional Sensing and Polarization* , 2003, Journal of Biological Chemistry.

[67]  Eberhard Bodenschatz,et al.  A bistable mechanism for directional sensing , 2008 .

[68]  Marc W Kirschner,et al.  An Actin-Based Wave Generator Organizes Cell Motility , 2007, PLoS biology.

[69]  W. Rappel,et al.  Dictyostelium discoideum chemotaxis: threshold for directed motion. , 2006, European journal of cell biology.

[70]  R. Skupsky,et al.  Distinguishing modes of eukaryotic gradient sensing. , 2005, Biophysical journal.

[71]  B. Kuhlman,et al.  A genetically-encoded photoactivatable Rac controls the motility of living cells , 2009, Nature.

[72]  Kevan M. Shokat,et al.  To stabilize neutrophil polarity, PIP3 and Cdc42 augment RhoA activity at the back as well as signals at the front , 2006, The Journal of cell biology.

[73]  C. Parent,et al.  Making all the right moves: chemotaxis in neutrophils and Dictyostelium. , 2004, Current opinion in cell biology.

[74]  Christopher Janetopoulos,et al.  Directional sensing during chemotaxis , 2008, FEBS letters.

[75]  Jason M Haugh,et al.  Spatial analysis of 3' phosphoinositide signaling in living fibroblasts: II. Parameter estimates for individual cells from experiments. , 2004, Biophysical journal.

[76]  Ned S Wingreen,et al.  Accuracy of direct gradient sensing by cell-surface receptors. , 2009, Progress in biophysics and molecular biology.

[77]  Bob Goldstein,et al.  The PAR proteins: fundamental players in animal cell polarization. , 2007, Developmental cell.

[78]  P. Fisher,et al.  Quantitative analysis of cell motility and chemotaxis in Dictyostelium discoideum by using an image processing system and a novel chemotaxis chamber providing stationary chemical gradients , 1989, The Journal of cell biology.

[79]  Martin Bastmeyer,et al.  Mechanisms of gradient detection: a comparison of axon pathfinding with eukaryotic cell migration. , 2007, International review of cytology.

[80]  D. Odde,et al.  Potential for Control of Signaling Pathways via Cell Size and Shape , 2006, Current Biology.

[81]  Gary G. Borisy,et al.  Self-polarization and directional motility of cytoplasm , 1999, Current Biology.

[82]  M. Toner,et al.  Adaptive-control model for neutrophil orientation in the direction of chemical gradients. , 2009, Biophysical journal.

[83]  Attila Csikász-Nagy,et al.  Spatial controls for growth zone formation during the fission yeast cell cycle , 2008, Yeast.

[84]  Leah Edelstein-Keshet,et al.  Phosphoinositides and Rho proteins spatially regulate actin polymerization to initiate and maintain directed movement in a one-dimensional model of a motile cell. , 2007, Biophysical journal.

[85]  Christopher A. Voigt,et al.  Spatiotemporal Control of Cell Signalling Using A Light-Switchable Protein Interaction , 2009, Nature.

[86]  H. Meinhardt,et al.  A theory of biological pattern formation , 1972, Kybernetik.

[87]  Pablo A Iglesias,et al.  Navigating through models of chemotaxis. , 2008, Current opinion in cell biology.

[88]  E. Bi,et al.  Central Roles of Small GTPases in the Development of Cell Polarity in Yeast and Beyond , 2007, Microbiology and Molecular Biology Reviews.

[89]  P. Iglesias,et al.  Chemoattractant-induced phosphatidylinositol 3,4,5-trisphosphate accumulation is spatially amplified and adapts, independent of the actin cytoskeleton , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[90]  M. Welch,et al.  Plasma membrane organization is essential for balancing competing pseudopod- and uropod-promoting signals during neutrophil polarization and migration. , 2005, Molecular biology of the cell.

[91]  John J Rhoden,et al.  Spontaneous phosphoinositide 3-kinase signaling dynamics drive spreading and random migration of fibroblasts , 2009, Journal of Cell Science.

[92]  J. Ferrell,et al.  Interlinked Fast and Slow Positive Feedback Loops Drive Reliable Cell Decisions , 2005, Science.

[93]  Alexandra Jilkine,et al.  Mathematical Model for Spatial Segregation of the Rho-Family GTPases Based on Inhibitory Crosstalk , 2007, Bulletin of mathematical biology.

[94]  Onn Brandman,et al.  Feedback Loops Shape Cellular Signals in Space and Time , 2008, Science.

[95]  C. Parent,et al.  A cell's sense of direction. , 1999, Science.

[96]  W. Rappel,et al.  Receptor noise limitations on chemotactic sensing , 2008, Proceedings of the National Academy of Sciences.

[97]  Gaudenz Danuser,et al.  Actin–myosin network reorganization breaks symmetry at the cell rear to spontaneously initiate polarized cell motility , 2007, The Journal of cell biology.

[98]  Brian D. Slaughter,et al.  Symmetry breaking in the life cycle of the budding yeast. , 2009, Cold Spring Harbor perspectives in biology.

[99]  Thomas Schmidt,et al.  Robust cell polarity is a dynamic state established by coupling transport and GTPase signaling , 2004, The Journal of cell biology.

[100]  Sigurd B. Angenent,et al.  On the spontaneous emergence of cell polarity , 2008, Nature.

[101]  P. V. van Haastert,et al.  A stochastic model for chemotaxis based on the ordered extension of pseudopods. , 2010, Biophysical journal.

[102]  P. Devreotes,et al.  Signaling pathways mediating chemotaxis in the social amoeba, Dictyostelium discoideum. , 2006, European journal of cell biology.

[103]  Shin Ishii,et al.  A molecular model for axon guidance based on cross talk between rho GTPases. , 2005, Biophysical journal.

[104]  Richard A. Firtel,et al.  G protein–independent Ras/PI3K/F-actin circuit regulates basic cell motility , 2007, The Journal of cell biology.

[105]  A. Hall,et al.  Rho GTPases and the actin cytoskeleton. , 1998, Science.

[106]  Jason M. Haugh,et al.  Quantitative elucidation of a distinct spatial gradient-sensing mechanism in fibroblasts , 2005, The Journal of cell biology.

[107]  A. M. Turing,et al.  The chemical basis of morphogenesis , 1952, Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.

[108]  Amy S. Gladfelter,et al.  Scaffold-mediated symmetry breaking by Cdc42p , 2003, Nature Cell Biology.

[109]  Olivier Pertz,et al.  Neutrophil polarization: spatiotemporal dynamics of RhoA activity support a self-organizing mechanism. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[110]  Kozo Kaibuchi,et al.  [Neuronal polarity]. , 2008, Tanpakushitsu kakusan koso. Protein, nucleic acid, enzyme.

[111]  Jingsong Xu,et al.  Divergent Signals and Cytoskeletal Assemblies Regulate Self-Organizing Polarity in Neutrophils , 2003, Cell.