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Role of the Cytoskeleton in Growth Cone Motility and Axonal Elongation Jean F

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Role of the Cytoskeleton in Growth Cone Motility and Axonal Elongation Jean F seminars in THE NEUROSCIENCES, Vol 8, 1996: pp 67–80 Role of the cytoskeleton in growth cone motility and axonal elongation Jean F. Challacombe, Diane M. Snow and Paul C. Letourneau During axonal pathfinding, the direction of nerve fiber determining them. Then we present our recent extension is established by the growth cone, the motile investigations of proteoglycan-mediated growth cone structure at the distal tip of an elongating axon. It is the inhibition and turning, suggesting (1) that filopodial growth cone that navigates and directs axonal outgrowth by contact with chondroitin sulfate proteoglycan (CSPG) detecting and responding to complex molecular cues in the elicits changes in microtubule bundling and align- nervous system environment. Changes in growth cone ment, and (2) that growth cones with deficient behavior and morphology that result from contact with these filopodia alter their direction of migration in cues depend on the regulated assembly and dynamic response to the inhibitory effects of CSPG by side- reorganization of actin filaments and microtubules. stepping instead of turning, implying that filopodia Therefore, an understanding of growth cone guidance are necessary for normal microtubule reorientation at requires resolution of the cytoskeletal rearrangements that fibronectin (FN)/CSPG borders. 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. Growth cone motility and actin filaments Key words: growth cone / cytoskeleton / actin filaments / Growth cones navigate by constantly extending and microtubules / proteoglycan retracting sensory protrusions in the form of broad flattened lamellipodia and finger-like filopodia, which ©1996 Academic Press Ltd comprise the leading edge or peripheral domain. As illustrated in Figure 1, the dynamic protrusive THE FUNCTIONAL ORGANIZATION of the adult nervous behavior of a navigating growth cone is based on actin system depends upon the connections formed during filament assembly at the leading edge, retrograde flow development, when axons grow out from neuronal of assembled actin filaments, and proximal dis- cell bodies and extend along specific pathways to assembly.8-13 Actin filaments are organized into two unite with their targets. This directed axonal elonga- populations at the leading edge: long bundled fila- tion results from the exploratory behavior of motile ments in filopodia, and a branching network extend- structures at the axon tips, the growth cones. Growth ing throughout lamellipodia.14 The dynamics of actin cones establish the direction of axonal elongation by filament assembly, disassembly, and organization into detecting and responding to signals, or guidance bundles and networks are influenced by actin-binding cues, in nervous system environment. Navigating proteins (reviewed in refs 10, 15-17). growth cones are highly dynamic, displaying complex Protrusive force is generated at the leading edge by behaviors during contact with specific guidance cues, actin filament dynamics and/or by actin–myosin such as cell surface and extracellular matrix mole- interactions. In the absence of substratum attach- 1-7 cules. Growth cone behaviors (protrusion, retrac- ments, these forces result in the retrograde flow of tion, branching and turning) depend on the dynamic actin filaments.9 Actin filament polymerization near reorganization of the cytoskeleton, which is composed the plasma membrane is coupled to ATP hydrolysis, of actin filaments and microtubules. In the first part of which can provide the power to move polymers this article, we describe the basic properties of growth rearward when they are prevented from forward cones, emphasizing the role of the cytoskeleton in elongation by the membrane.8,10 Additionally, myo- sins I and II have been localized at the leading edge of From the Department of Cell Biology and Neuroanatomy, The 18-22 University of Minnesota, Minneapolis, MN 55455, USA growth cones. This suggests that membrane- ©1996 Academic Press Ltd associated myosin molecules may interact with actin 1044-5765/96/020067 + 14 $18.00/0 filaments at the leading edge of growth cones to 67 J. F. Challacombe et al Figure 1. Substratum–cytoskeletal coupling model of growth cone advance. Actin dynamics of a neuronal growth cone lamellipodium are represented by a steady state composed of three superimposed processes (open arrows): actin filament assembly at the leading edge, actin filament disassembly at the back of the P domain, and retrograde flow of actin filaments at a rate matching assembly and disassembly. ‘Clutch’ protein complexes may regulate the degree of mechanical coupling between the actin filament network in the lamellipodium and adhesive bonds between surface ligands and extrinsic substrata. When the ‘clutch’ engages the filament network to the cell– substratum contact, the retrograde flow is attenuated, while actin disassembly continues. This removes impedance and accelerates the advance of microtubules by polymerization and/or transport. Reproduced from Neuron 14, 763-771 with permission of Dr P. Forscher and Cell Press. produce the tension that pulls the elongating neurite Axonal elongation and microtubules forward.10,13,18,21,23,24 A current model (Figure 1) explains the role of Microtubules are the major cytoskeletal components tension and substratum attachments in growth cone of axons, serving as tracks for the axonal transport of advance; this model is based on evidence that the membranous organelles,29 and contributing to axonal cytoplasmic domains of cell adhesion molecules can structure by virtue of their rigidity and resistance to be coupled to actin filaments by ‘clutch’ protein compression.30,31 The organization of microtubules complexes.9,13,25,26 When the clutch protein com- in growth cones suggests that they are also instru- plexes are disengaged, actin filaments and cell adhe- mental in axonal formation behind the advancing sion molecules are uncoupled, myosin–actin inter- growth cone.32-35 The three microtubule activities that actions cannot exert tension on the substratum, and contribute to axonal elongation are dynamics, trans- actin filaments flow rearward. However, when clutch location (or advance), and bundling.36 proteins link actin filaments to cell adhesion mole- cules, which are bound to the substratum, the tension Microtubule dynamics produced between myosin and actin filaments is transduced into growth cone advance. Different In vitro and in cells, microtubules grow and shrink protein complexes link the various cell adhesion continuously, a process called dynamic instability.37 molecules to actin filaments.25 Recent evidence sug- Microtubules can also undergo treadmilling, where gests that the involvement of actin filaments in growth net assembly and disassembly occur simultaneously at cone navigation depends on the nature of the opposite ends.38 These dynamic processes can be substratum and on how effectively clutch proteins link regulated by the gain and loss of a stabilizing GTP cap the different cell adhesion receptors to actin from microtubule ends,37,39 by interactions of various filaments.26-28 microtubule-associated proteins with microtu- bules,40-45 or by the tubulin isotype composition.46 In addition, microtubule dynamics are linked to post- 68 69 The cytoskeleton in growth conenavigation The cytoskeletoningrowth Figure 2. Arrangement of the cytoskeleton in growth cones elongating on FN (A–C), at a FN/CSPG border (D–F), and turning to migrate along the border (G–I). Laser scanning confocal optical sections were projected onto the same plane to show all labeling for each cytoskeletal component. Stable microtubules are labeled with polyclonal antibodies that recognize detyrosinated α-tubulin (A,D,G), actin filaments with rhodamine-phalloidin (B,E,H), and dynamic microtubules with a monoclonal antibody directed against tyrosinated α-tubulin (C,F,I). The rhodamine-labeled CSPG stripe is shown in E and H. Prior to contact with the CSPG stripe, stable microtubules are confined to the central region of the growth cone (A), while dynamic microtubules (C) overlap with actin filaments (B) at the bases of filopodia. The arrows in panel C point to dynamic microtubule ends that overlap with filopodial actin filament bundles. As growth cones begin to turn at the FN/CSPG border, the labeling of stable microtubules overlaps with that of dynamic microtubules (compare D and F). The area of overlap is indicated by arrows in panels D and F. Growth cones that have turned contain tightly bundled stable and dynamic microtubules extending along the border and into actin-dense regions at the growth cone tip (G–I). For each set of images, the scale bar on the bottom image represents 10 µm J. F. Challacombe et al translational modifications of tubulin, such that stable the above studies used various neuronal types, it has microtubules can be distinguished from dynamic ones been suggested that neurons from different organ- by specific biochemical markers.47 isms use different means to advance microtu- One aspect of neuronal differentiation is that bules;62,63 this may be related to the growth rates of microtubules become resistant, or stable, to dis- these neurons. For example, tubulin polymers might assembly by cold and certain drugs.42,48-50 While the be translocated in fast growing frog neurons62 while exact mechanism responsible for microtubule stabili- in slower growing neurons of mice, grasshoppers62 zation is unknown, numerous studies implicate
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