Mechanisms of Gradient Detection: A Comparison of Axon Pathfinding with Eukaryotic Cell Migration

Philipsborn, Anne C. von; Bastmeyer, Martin

doi:10.1016/s0074-7696(07)63001-0

Cited by 58 publications

(57 citation statements)

References 207 publications

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“…This naturally awards peripheral receptors greater influence than those closer to the polarization axis. Although these authors focused on eukaryotic cell chemotaxis, similarities with the signaling networks underlying growth cone chemotaxis suggests that their results may also be relevant for growth cones (8,44). The decision process itself, i.e., choosing the side on which the weighted signal is greatest, could then be implemented through adaptation and positive feedback, tuned to the appropriate length scale (8).…”

Section: Discussionmentioning

confidence: 99%

A Bayesian model predicts the response of axons to molecular gradients

Mortimer

Feldner

Vaughan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

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Axon guidance by molecular gradients plays a crucial role in wiring up the nervous system. However, the mechanisms axons use to detect gradients are largely unknown. We first develop a Bayesian ''ideal observer'' analysis of gradient detection by axons, based on the hypothesis that a principal constraint on gradient detection is intrinsic receptor binding noise. Second, from this model, we derive an equation predicting how the degree of response of an axon to a gradient should vary with gradient steepness and absolute concentration. Third, we confirm this prediction quantitatively by performing the first systematic experimental analysis of how axonal response varies with both these quantities. These experiments demonstrate a degree of sensitivity much higher than previously reported for any chemotacting system. Together, these results reveal both the quantitative constraints that must be satisfied for effective axonal guidance and the computational principles that may be used by the underlying signal transduction pathways, and allow predictions for the degree of response of axons to gradients in a wide variety of in vivo and in vitro settings.axon guidance ͉ chemotaxis ͉ growth cone ͉ nerve growth factor ͉ nerve regeneration E ndogenous chemical gradients are a key source of information used by developing axons when wiring up the nervous system. Furthermore, artificially generated gradients are a potential therapy for restoring connectivity after neural injury. Many of the molecular gradients that direct axons in the developing nervous system have recently been identified, together with some of the signaling pathways through which they operate (1-8). However, our understanding of the mechanisms by which axons actually detect gradients remains qualitative. This limits our ability to predict both the response of axons when gradients are perturbed and the optimal parameters for promoting regrowth after injury.To be guided by a gradient, axons must be able to detect small spatial variations in receptor binding. This requires integrating signals from spatially distributed receptors to make a decision as to the direction of the gradient. Resources within the growth cone can then be marshaled appropriately by this information, for instance, via the production of steep gradients of intracellular signaling molecules (8). Although there is evidence for a role for gradients of molecules such as Ca 2ϩ in this latter step (9, 10), very little is known about the computations required to accurately make the initial decision.What constrains the ability of an axon to make a decision regarding gradient direction? Both experimental and computational work addressing chemotaxis in related systems such as bacteria, leukocytes, and Dictyostelium has identified the fundamental role of noise in limiting gradient perception. Noise can arise from low numbers of ligand molecules, from the stochastic nature of receptor binding, and from intracellular signaling pathways (11-16). Such constraints must also apply to axonal gradient sensing (17...

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Section: Discussionmentioning

confidence: 99%

A Bayesian model predicts the response of axons to molecular gradients

Mortimer

Feldner

Vaughan

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

164

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“…4A,B), was first described in bacteria by Pfeffer (Pfeffer, 1884) and later in phagocytic leucocytes by Metchnikoff (Metchnikoff, 1893). Since then, chemotaxis has been a subject of intense research in both prokaryotic (Hazelbauer, 2012) and eukaryotic cells, including the free-living amoeba Dictyostelium discoideum, mammalian leukocytes, fibroblasts and neurons (Swaney et al, 2010;von Philipsborn and Bastmeyer, 2007;Vorotnikov, 2011). Despite exhibiting different modes of cell locomotion (ameboid in D. discoideum and leukocytes; mesenchymal in fibroblasts) and utilising different signal transduction mechanisms [G protein-coupled receptor (GPCR)-dependent in D. discoideum and leukocytes, and receptor tyrosine kinase (RTK)-dependent in fibroblasts], most in vitro models of eukaryotic chemotaxis share three general principles.…”

Section: Directed Cell Migration Via Chemotaxismentioning

confidence: 99%

Cell migration: from tissue culture to embryos

2014

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Cell migration is a fundamental process that occurs during embryo development. Classic studies using in vitro culture systems have been instrumental in dissecting the principles of cell motility and highlighting how cells make use of topographical features of the substrate, cell-cell contacts, and chemical and physical environmental signals to direct their locomotion. Here, we review the guidance principles of in vitro cell locomotion and examine how they control directed cell migration in vivo during development. We focus on developmental examples in which individual guidance mechanisms have been clearly dissected, and for which the interactions among guidance cues have been explored. We also discuss how the migratory behaviours elicited by guidance mechanisms generate the stereotypical patterns of migration that shape tissues in the developing embryo.

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“…Gradient sensing depends on the translation of an external gradient into an amplified intracellular signal gradient (48). This signaling asymmetry leads to an asymmetry in cell shape accomplished by cytoskeleton rearrangement.…”

Section: Discussionmentioning

confidence: 99%

Asymmetrical Macromolecular Complex Formation of Lysophosphatidic Acid Receptor 2 (LPA2) Mediates Gradient Sensing in Fibroblasts

Ren

Moon

Zhang

et al. 2014

Journal of Biological Chemistry

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Background: Chemotaxis is a fundamental process in many physiological and pathological events. Results: An LPA gradient induces a spatiotemporally restricted decrease in the mobility of LPA 2 indicative of its cytoplasmic anchorage to NHERF2, the cytoskeleton and PLC␤, which causes a gradient of localized Ca 2ϩ puffs. Conclusion: Asymmetrical macromolecular complex formation by LPA 2 mediates gradient sensing. Significance: Our finding provides a new mechanistic basis to help understand chemotactic gradient sensing.

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Mechanisms of Gradient Detection: A Comparison of Axon Pathfinding with Eukaryotic Cell Migration

Cited by 58 publications

References 207 publications

A Bayesian model predicts the response of axons to molecular gradients

A Bayesian model predicts the response of axons to molecular gradients

Cell migration: from tissue culture to embryos

Asymmetrical Macromolecular Complex Formation of Lysophosphatidic Acid Receptor 2 (LPA2) Mediates Gradient Sensing in Fibroblasts

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