The Experts below are selected from a list of 327 Experts worldwide ranked by ideXlab platform
Stephen M. Strittmatter - One of the best experts on this subject based on the ideXlab platform.
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semaphorin3a enhances endocytosis at sites of receptor f actin colocalization during Growth Cone collapse
Journal of Cell Biology, 2000Co-Authors: Alyson E. Fournier, Fumio Nakamura, Robert G. Kalb, Yoshio Goshima, Susumu Kawamoto, Stephen M. StrittmatterAbstract:Axonal Growth Cone collapse is accompanied by a reduction in filopodial F-actin. We demonstrate here that semaphorin 3A (Sema3A) induces a coordinated rearrangement of Sema3A receptors and F-actin during Growth Cone collapse. Differential interference contrast microscopy reveals that some sites of Sema3A-induced F-actin reorganization correlate with discrete vacuoles, structures involved in endocytosis. Endocytosis of FITC-dextran by the Growth Cone is enhanced during Sema3A treatment, and sites of dextran accumulation colocalize with actin-rich vacuoles and ridges of membrane. Furthermore, the Sema3A receptor proteins, neuropilin-1 and plexin, and the Sema3A signaling molecule, rac1, also reorganize to vacuoles and membrane ridges after Sema3A treatment. These data support a model whereby Sema3A stimulates endocytosis by focal and coordinated rearrangement of receptor and cytoskeletal elements. Dextran accumulation is also increased in retinal ganglion cell (RGC) Growth Cones, in response to ephrin A5, and in RGC and DRG Growth Cones, in response to myelin and phorbol-ester. Therefore, enhanced endocytosis may be a general principle of physiologic Growth Cone collapse. We suggest that Growth Cone collapse is mediated by both actin filament rearrangements and alterations in membrane dynamics.
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Rho GTPases and axonal Growth Cone collapse.
Methods in enzymology, 2000Co-Authors: Alyson E. Fournier, Robert G. Kalb, Stephen M. StrittmatterAbstract:Publisher Summary This chapter describes Rho guanosine 5'-triphosphates (GTPases) and axonal Growth Cone collapse. The axonal Growth Cone is the specialized distal tip of the extending axon and consists of both lamellipodia and filopodia structures. Control of Growth Cone dynamics is critical for neurite outGrowth and guidance. Modulating the activity state of Rho, Rac, and Cdc42 in neurons can modulate the Growth Cone response to collapsing agents. The chapter discusses two methods of introducing Rho family GTPase into cultured neurons. These methods are designed to facilitate an analysis of the role of such GTPase in Growth Cone collapse by axonal guidance factors. The chapter presents a protocol to measure levels of activated Rac and Cdc42 in cultured neurons following the introduction of Growth Cone collapsing agents.
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Neuropilin-1 Extracellular Domains Mediate Semaphorin D/III-Induced Growth Cone Collapse
Neuron, 1998Co-Authors: Fumio Nakamura, Takuya Takahashi, Masaki Tanaka, Robert G. Kalb, Stephen M. StrittmatterAbstract:Abstract Somatosensory axon outGrowth is repulsed when soluble semaphorin D (semD) binds to Growth Cone neuropilin-1 (Npn-1). Here, semD ligand binding studies of Npn-1 mutants demonstrate that the sema domain binds to the amino-terminal quarter, or complement-binding (CUB) domain, of Npn-1. By herpes simplex virus– (HSV-) mediated expression of Npn-1 mutants in chick retinal ganglion cells, we show that semD-induced Growth Cone collapse requires two segments of the ectodomain of Npn-1, the CUB domain and the juxtamembrane portion, or MAM (meprin, A5, μ) domain. In contrast, the transmembrane segment and cytoplasmic tail of Npn-1 are not required for biologic activity. These data imply that the CUB and MAM ectodomains of Npn-1 interact with another transmembrane Growth Cone protein that in turn transduces a semD signal into axon repulsion.
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rac1 mediates collapsin 1 induced Growth Cone collapse
The Journal of Neuroscience, 1997Co-Authors: Zhao Jin, Stephen M. StrittmatterAbstract:Collapsin-1 or semaphorin III(D) inhibits axonal outGrowth by collapsing the lamellipodial and filopodial structures of the neuronal Growth Cones. Because Growth Cone collapse is associated with actin depolymerization, we considered whether small GTP-binding proteins of the rho subfamily might participate in collapsin-1 signal transduction. Recombinant rho, rac1, and cdc42 proteins were triturated into embryonic chick (DRG) neurons. Constitutively active rac1 increases the proportion of collapsed Growth Cones, and dominant negative rac1 inhibits collapsin-1-induced collapse of Growth Cones and collapsin-1 inhibition of neurite outGrowth. DRG neurons treated with dominant negative rac1 remain sensitive to myelin-induced Growth Cone collapse. Similar mutants of cdc42 do not alter Growth Cone structure, neurite elongation, or collapsin-1 sensitivity. Whereas the addition of activated rho has no effect, the inhibition of rho with Clostridium botulinum C3 transferase stimulates the outGrowth of DRG neurites. C3 transferase-treated Growth Cones exhibit little or no lamellipodial spreading and are minimally responsive to collapsin-1 and myelin. These data demonstrate a prominent role for rho and rac1 in modulating Growth Cone motility and indicate that rac1 may mediate collapsin-1 action.
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Signal Transduction at the Neuronal Growth Cone
The Neuroscientist, 1996Co-Authors: Stephen M. StrittmatterAbstract:Nervous system development depends on axonal Growth Cone recognition of extracellular guidance clues and transduction of this information into directed Growth. Major advances have been made in characterizing the extracellular molecules that serve as signals for growing axons, in correlating fluctuations of Ca,++ with motility, and in demonstrating the actin-dependent basis of Growth Cone motility. The intracellular events that immediately follow ligand-receptor interaction at the Growth Cone are largely undetermined. Molecules of the integrin family, the cadherin family, and the cell adhesion molecule family organize cytoskeletal changes directly but also may initiate signaling cascades involving diffusible messengers. Heterotrimeric G proteins are highly concentrated in the Growth Cone membrane and can account for the initial steps in signal transduction for several neurotransmitters that regulate axonal Growth. GAP-43 enhances the sensitivity of G protein-mediated transduction. Molecules inhibitory for ...
Paul C. Letourneau - One of the best experts on this subject based on the ideXlab platform.
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actin dynamics in Growth Cone motility and navigation
Journal of Neurochemistry, 2014Co-Authors: Timothy M. Gomez, Paul C. LetourneauAbstract:Motile Growth Cones lead growing axons through developing tissues to synaptic targets. These behaviors depend on the organization and dynamics of actin filaments that fill the Growth Cone leading margin [peripheral (P-) domain]. Actin filament organization in Growth Cones is regulated by actin-binding proteins that control all aspects of filament assembly, turnover, interactions with other filaments and cytoplasmic components, and participation in producing mechanical forces. Actin filament polymerization drives protrusion of sensory filopodia and lamellipodia, and actin filament connections to the plasma membrane link the filament network to adhesive contacts of filopodia and lamellipodia with other surfaces. These contacts stabilize protrusions and transduce mechanical forces generated by actomyosin activity into traction that pulls an elongating axon along the path toward its target. Adhesive ligands and extrinsic guidance cues bind Growth Cone receptors and trigger signaling activities involving Rho GTPases, kinases, phosphatases, cyclic nucleotides, and [Ca++] fluxes. These signals regulate actin-binding proteins to locally modulate actin polymerization, interactions, and force transduction to steer the Growth Cone leading margin toward the sources of attractive cues and away from repellent guidance cues.
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Regulation of Growth Cone Actin Filaments by Guidance Cues
Journal of neurobiology, 2003Co-Authors: Gianluca Gallo, Paul C. LetourneauAbstract:The motile behaviors of Growth Cones at the ends of elongating axons determine pathways of axonal connections in developing nervous systems. Growth Cones express receptors for molecular guidance cues in the local environment, and receptor-guidance cue binding initiates cytoplasmic signaling that regulates the cytoskeleton to control Growth Cone advance, turning, and branching behaviors. The dynamic actin filaments of Growth Cones are frequently targets of this regulatory signaling. Rho GTPases are key mediators of signaling by guidance cues, although much remains to be learned about how Growth Cone responses are orchestrated by Rho GTPase signaling to change the dynamics of polymerization, transport, and disassembly of actin filaments. Binding of neurotrophins to Trk and p75 receptors on Growth Cones triggers changes in actin filament dynamics to regulate several aspects of Growth Cone behaviors. Activation of Trk receptors mediates local accumulation of actin filaments, while neurotrophin binding to p75 triggers local decrease in RhoA signaling that promotes lengthening of filopodia. Semaphorin IIIA and ephrin-A2 are guidance cues that trigger avoidance or repulsion of certain Growth Cones, and in vitro responses to these proteins include Growth Cone collapse. Dynamic changes in the activities of Rho GTPases appear to mediate responses to these cues, although it remains unclear what the changes are in actin filament distribution and dynamic reorganization that result in Growth Cone collapse. Growth Cones in vivo simultaneously encounter positive and negative guidance cues, and thus, Growth Cone behaviors during axonal pathfinding reflect the complex integration of multiple signaling activities.
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rac1 mediated endocytosis during ephrin a2 and semaphorin 3a induced Growth Cone collapse
The Journal of Neuroscience, 2002Co-Authors: William M Jurney, Gianluca Gallo, Paul C. Letourneau, Steven C McloonAbstract:Negative guidance molecules are important for guiding the Growth of axons and ultimately for determining the wiring pattern in the developing nervous system. In tissue culture, Growth Cones at the tips of growing axons collapse in response to negative guidance molecules, such as ephrin-A2 and semaphorin 3A. The small GTPase Rac1 is involved in Growth Cone collapse, but the nature of its role is not clear. Rac1 activity assays showed that Rac1 is transiently inactivated after treatment with ephrin-A2. Ephrin-induced Growth Cone collapse, however, correlated with resumption of Rac1 activity. We demonstrate that Rac1 is required for endocytosis of the Growth Cone plasma membrane and reorganization of F-actin but not for the depolymerization of F-actin during Growth Cone collapse in response to ephrin-A2 and semaphorin 3A. Rac1, however, does not regulate constitutive endocytosis in Growth Cones. These findings show that in response to negative guidance molecules, the function of Rac1 changes from promoting actin polymerization associated with axon Growth to driving endocytosis of the plasma membrane, resulting in Growth Cone collapse. Furthermore, Rac1 antisense injected into the embryonic chick eye in vivo caused the retinotectal projection to develop without normal topography in a manner consistent with Rac1 having an obligatory role in mediating ephrin signaling.
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Role of the cytoskeleton in Growth Cone motility and axonal elongation
Seminars in Neuroscience, 1996Co-Authors: Jean F. Challacombe, Diane M. Snow, Paul C. LetourneauAbstract:Abstract During axonal pathfinding, the direction of nerve fiber extension is established by the Growth Cone, the motile structure at the distal tip of an elongating axon. It is the Growth Cone that navigates and directs axonal outGrowth by detecting and responding to complex molecular cues in the nervous system environment. Changes in Growth Cone behavior and morphology that result from contact with these cues depend on the regulated assembly and dynamic reorganization of actin filaments and microtubules. Therefore, an understanding of Growth Cone guidance requires resolution of the cytoskeletal rearrangements that occur as navigating Growth Cones respond to stimulatory and inhibitory molecular signals in their milieu. In this review, we discuss the role of the cytoskeleton in Growth Cone navigation.
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Growth Cone motility.
Current opinion in cell biology, 1992Co-Authors: Christopher Cypher, Paul C. LetourneauAbstract:Neurons obtain their stereotyped morphologies and connections as a result of Growth Cone migration. In the past year, studies on Growth Cone migration and pathfinding have helped to define certain properties of cytoskeletal filaments and cell membranes that may be important in Growth Cone function. Antisense mRNAs have proved to be particularly useful for examining the roles of specific neurite proteins.
Hiroyuki Kamiguchi - One of the best experts on this subject based on the ideXlab platform.
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Second messenger networks for accurate Growth Cone guidance.
Developmental neurobiology, 2013Co-Authors: Hiroki Akiyama, Hiroyuki KamiguchiAbstract:Growth Cones are able to navigate over long distances to find their appropriate target by following guidance cues that are often presented to them in the form of an extracellular gradient. These external cues are converted into gradients of specific signaling molecules inside Growth Cones, while at the same time these internal signals are amplified. The amplified instruction is then used to generate asymmetric changes in the Growth Cone turning machinery so that one side of the Growth Cone migrates at a rate faster than the other side, and thus the Growth Cone turns toward or away from the external cue. This review examines how signal specification and amplification can be achieved inside the Growth Cone by multiple second messenger signaling pathways activated downstream of guidance cues. These include the calcium ion, cyclic nucleotide, and phosphatidylinositol signaling pathways.
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Second messengers and membrane trafficking direct and organize Growth Cone steering
Nature Reviews Neuroscience, 2011Co-Authors: Takuro Tojima, John R Henley, Jacob H. Hines, Hiroyuki KamiguchiAbstract:The Growth Cones of developing axons are guided towards their targets by gradients of cues. Kamiguchi and colleagues propose a mechanism for this process whereby cues trigger an alteration in the balance of endocytosis and exocytosis on one side of the Growth Cone, biasing the direction of turning. During neural development, graded distribution of extracellular cues in the microenvironment causes asymmetric generation of second messengers across the Growth Cone in order to guide the axon along its correct path. Asymmetrically generated Ca^2+ signals are sufficient to initiate Growth Cone turning toward (attraction) or away from (repulsion) the side with higher Ca^2+ concentrations. Gating of differential sets of Ca^2+ channels, which are regulated counteractively by cyclic AMP and cyclic GMP, can be responsible for switching between Growth Cone attraction and repulsion. We propose that high-amplitude Ca^2+ elevation involving Ca^2+ release from the endoplasmic reticulum mediates attractive guidance, whereas low-amplitude Ca^2+ influx that does not trigger substantial Ca^2+ release from the endoplasmic reticulum mediates repulsive guidance. Shallow concentration gradients of guidance cues can shape Growth Cone Ca^2+ signals for precise navigational responses. This process may depend on second messenger networks including positive-feedback augmentation between Ca^2+ and cyclic AMP. Repulsive Ca^2+ signals cause asymmetric clathrin-mediated endocytosis across the Growth Cone with more endocytosis on the side with elevated Ca^2+. Attractive Ca^2+ signals promote centrifugal transport of membrane vesicles and their subsequent exocytosis mediated by vesicle-associated membrane protein 2 on the side with elevated Ca^2+. We propose that asymmetric membrane trafficking is an early and instructive step in the initiation of Growth Cone turning. Localized imbalance between endocytosis and exocytosis may trigger redistribution of adhesion molecules, cytoskeletal components and bulk membrane, which would potentiate asymmetric traction and protrusion forces essential for turning. The Growth Cone in complex environmental terrain in vivo must integrate multiple guidance signals simultaneously to navigate with high fidelity. Spatiotemporally regulated interactions among Ca^2+ and cyclic nucleotides potentially have crucial roles in this integration process, which will need to be scrutinized by quantitative imaging of multiple second messengers in navigating Growth Cones. Graded distributions of extracellular cues guide developing axons toward their targets. A network of second messengers — Ca^2+ and cyclic nucleotides — shapes cue-derived information into either attractive or repulsive signals that steer Growth Cones bidirectionally. Emerging evidence suggests that such guidance signals create a localized imbalance between exocytosis and endocytosis, which in turn redirects membrane, adhesion and cytoskeletal components asymmetrically across the Growth Cone to bias the direction of axon extension. These recent advances allow us to propose a unifying model of how the Growth Cone translates shallow gradients of environmental information into polarized activity of the steering machinery for axon guidance.
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Polarizing membrane dynamics and adhesion for Growth Cone navigation.
Molecular and Cellular Neuroscience, 2011Co-Authors: Rurika Itofusa, Hiroyuki KamiguchiAbstract:Neuronal network formation relies on the motile behavior of Growth Cones at the tip of navigating axons. Accumulating evidence indicates that Growth Cone motility requires spatially controlled endocytosis and exocytosis that can redistribute bulk membrane and functional cargos such as cell adhesion molecules. For axon elongation, the Growth Cone recycles cell adhesion molecules from its rear to its leading front through endosomes, thereby polarizing Growth Cone adhesiveness along the axis of migration direction. In response to extracellular guidance cues, the Growth Cone turns by retrieving membrane components from the retractive side or by supplying them to the side facing the new direction. We propose that polarized membrane trafficking creates adhesion gradients along and across the front-to-rear axis of Growth Cones that are essential for axon elongation and turning, respectively. This review will examine how Growth Cone adhesiveness can be patterned by spatially coordinated endocytosis and exocytosis of cell adhesion molecules. This article is part of a Special Issue entitled 'Neuronal Function'.
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Intracellular Mechanisms Underlying Neuronal Growth Cone Guidance
Seibutsu Butsuri, 2011Co-Authors: Takuro Tojima, Hiroki Akiyama, Hiroyuki KamiguchiAbstract:The formation of neuronal networks depends critically on the Growth Cone, a motile ameboid structure at the tip of elongating axon. Graded distributions of extracellular guidance cues attract or repel the Growth Cone by generating asymmetric cytosolic Ca2+ signals across the Growth Cone. We showed that the directional polarity of Growth Cone guidance is determined by the source of Ca2+ signals. We also demonstrated that, downstream of Ca2+ signals, asymmetric exocytosis and endocytosis drive Growth Cone attraction and repulsion, respectively. These findings provide a novel concept that polarized membrane trafficking acts as an instructive mechanism to spatially localize the steering apparatus such as cytoskeletal components and adhesion molecules.
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The Driving Machinery for Growth Cone Navigation
Advances in Neurobiology, 2010Co-Authors: Takuro Tojima, Hiroyuki KamiguchiAbstract:The motility of neuronal Growth Cones plays a crucial role in the formation of neuronal circuit. For Growth Cone migration, the cytoskeleton and its associated motors generate traction force that is transmitted to the surrounding environment via cell adhesion molecules. The force transmission can be spatiotemporally controlled by a molecular clutch that mediates mechanical coupling of cell adhesion molecules and the actin cytoskeleton. Furthermore, intracellular membrane trafficking may control the supply and removal of membrane components in a spatially defined manner. In this chapter, we will argue that coordinated activity of these molecular events determines the speed and direction of axon Growth, with particular emphasis on how Ca2+ signals control the driving machinery for Growth Cone navigation.
David Van Vactor - One of the best experts on this subject based on the ideXlab platform.
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The trip of the tip: understanding the Growth Cone machinery
Nature Reviews Molecular Cell Biology, 2009Co-Authors: Laura Anne Lowery, David Van VactorAbstract:The central component in the road trip of axon guidance is the Growth Cone, a dynamic structure that is located at the tip of the growing axon. During its journey, the Growth Cone comprises both 'vehicle' and 'navigator'. Whereas the 'vehicle' maintains Growth Cone movement and contains the cytoskeletal structural elements of its framework, a motor to move forward and a mechanism to provide traction on the 'road', the 'navigator' aspect guides this system with spatial bias to translate environmental signals into directional movement. The understanding of the functions and regulation of the vehicle and navigator provides new insights into the cell biology of Growth Cone guidance. During axon guidance, the Growth Cone, which comprises both the 'vehicle' and the 'navigator', progresses through stages of protrusion, engorgement and consolidation to move forward in a spatially directed manner. Growth Cone guidance is an integrated process that requires both substrate-bound cues (such as cell adhesion molecules (CAMs), laminin and fibronectin) to provide the 'road' for traction, and chemotropic cues (such as netrins and semaphorins) that present 'road signs' for steering directions. Filamentous (F)-actin retrograde flow, which is driven by myosin II contractility in the transition (T) zone, and F-actin bundle treadmilling keep the Growth Cone engine idling and thus responsive to directional cues. Growth Cone receptor binding to an adhesive substrate leads to the formation of a complex that acts like a molecular 'clutch', which mechanically couples receptors and F-actin to stop retrograde flow and drives actin-based forward Growth Cone protrusion. Microtubules (MTs) have a role in steering the Growth Cone vehicle; individual peripheral (P) domain MTs might act as guidance sensors and carry signals to and from receptor binding sites, and bulk central (C) domain MTs steer Growth Cone advance. Live imaging studies suggest that the function of actin dynamics is to guide and control MTs to steer the Growth Cone in the right direction, and interactions between actin and MTs are tightly regulated. F-actin bundles regulate the activities of exploratory MTs, whereas F-actin arcs constrain C domain MTs. For spatial discontinuities in the environment to drive Growth Cone steering and, in particular, to accurately interpret numerous cues simultaneously, the Growth Cone navigation system integrates and translates the multiple environmental directions to locally modulate the dynamics of the cytoskeletal machinery. The Rho family of GTPases control cytoskeletal dynamics downstream of nearly all guidance signalling pathways, and they are spatially regulated by guanine nucleotide-exchange factors (GEFs) and GTPase-activating proteins (GAPs). Localized control of actin dynamics at the leading edge through actin-binding proteins, and coordination of MT–actin crosslinking, are two key outputs of the navigation system that are required for Growth Cone steering. The journey of the Growth Cone is similar to a vehicle on a road. Cytoskeletal elements form the 'motor' to move forward and provide traction on the road, whereas a 'navigator' system guides the vehicle to translate environmental signals into directional movement.
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the trip of the tip understanding the Growth Cone machinery
Nature Reviews Molecular Cell Biology, 2009Co-Authors: Laura Anne Lowery, David Van VactorAbstract:The central component in the road trip of axon guidance is the Growth Cone, a dynamic structure that is located at the tip of the growing axon. During its journey, the Growth Cone comprises both 'vehicle' and 'navigator'. Whereas the 'vehicle' maintains Growth Cone movement and contains the cytoskeletal structural elements of its framework, a motor to move forward and a mechanism to provide traction on the 'road', the 'navigator' aspect guides this system with spatial bias to translate environmental signals into directional movement. The understanding of the functions and regulation of the vehicle and navigator provides new insights into the cell biology of Growth Cone guidance.
Timothy M. Gomez - One of the best experts on this subject based on the ideXlab platform.
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Division of labor in the Growth Cone by DSCR1
The Journal of cell biology, 2016Co-Authors: Timothy S. Catlett, Timothy M. GomezAbstract:Local protein synthesis directs Growth Cone turning of nascent axons, but mechanisms governing this process within compact, largely autonomous microenvironments remain poorly understood. In this issue, Wang et al. (2016. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201510107) demonstrate that the calcineurin regulator Down syndrome critical region 1 protein modulates both basal neurite outGrowth and Growth Cone turning.
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Mechanochemical regulation of Growth Cone motility
Frontiers in cellular neuroscience, 2015Co-Authors: Patrick C. Kerstein, Robert H. Nichol, Timothy M. GomezAbstract:Neuronal Growth Cones are exquisite sensory-motor machines capable of transducing features contacted in their local extracellular environment into guided process extension during development. Extensive research has shown that chemical ligands activate cell surface receptors on Growth Cones leading to intracellular signals that direct cytoskeletal changes. However, the environment also provides mechanical support for Growth Cone adhesion and traction forces that stabilize leading edge protrusions. Interestingly, recent work suggests that both the mechanical properties of the environment and mechanical forces generated within Growth Cones influence axon guidance. In this review we discuss novel molecular mechanisms involved in Growth Cone force production and detection, and speculate how these processes may be necessary for the development of proper neuronal morphogenesis.
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actin dynamics in Growth Cone motility and navigation
Journal of Neurochemistry, 2014Co-Authors: Timothy M. Gomez, Paul C. LetourneauAbstract:Motile Growth Cones lead growing axons through developing tissues to synaptic targets. These behaviors depend on the organization and dynamics of actin filaments that fill the Growth Cone leading margin [peripheral (P-) domain]. Actin filament organization in Growth Cones is regulated by actin-binding proteins that control all aspects of filament assembly, turnover, interactions with other filaments and cytoplasmic components, and participation in producing mechanical forces. Actin filament polymerization drives protrusion of sensory filopodia and lamellipodia, and actin filament connections to the plasma membrane link the filament network to adhesive contacts of filopodia and lamellipodia with other surfaces. These contacts stabilize protrusions and transduce mechanical forces generated by actomyosin activity into traction that pulls an elongating axon along the path toward its target. Adhesive ligands and extrinsic guidance cues bind Growth Cone receptors and trigger signaling activities involving Rho GTPases, kinases, phosphatases, cyclic nucleotides, and [Ca++] fluxes. These signals regulate actin-binding proteins to locally modulate actin polymerization, interactions, and force transduction to steer the Growth Cone leading margin toward the sources of attractive cues and away from repellent guidance cues.
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filopodial calcium transients promote substrate dependent Growth Cone turning
Science, 2001Co-Authors: Timothy M. Gomez, Muming Poo, Estuardo Robles, Nicholas C SpitzerAbstract:Filopodia that extend from neuronal Growth Cones sample the environment for extracellular guidance cues, but the signals they transmit to Growth Cones are unknown. Filopodia were observed generating localized transient elevations of intracellular calcium ([Ca2+]i) that propagate back to the Growth Cone and stimulate global Ca2+ elevations. The frequency of filopodial Ca2+ transients was substrate-dependent and may be due in part to influx of Ca2+ through channels activated by integrin receptors. These transients slowed neurite outGrowth by reducing filopodial motility and promoted turning when stimulated differentially within filopodia on one side of the Growth Cone. These rapid signals appear to serve both as autonomous regulators of filopodial movement and as frequency-coded signals integrated within the Growth Cone and could be a common signaling process for many motile cells.
