REVIEW |
Correspondence to: James R. Bamburg, Dept. of Biochemistry and Molecular Biology, 1870 Campus Delivery, Colorado State University, Fort Collins, CO 80523-1870. E-mail: jbamburg@lamar.colostate.edu
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Summary |
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Nervous system development is reliant on neuronal pathfinding, the process in which axons are guided to their target cells by specific extracellular cues. The ability of neurons to extend over long distances in response to environmental guidance signals is made possible by the growth cone, a highly motile structure found at the end of neuronal processes. Growth cones detect directional cues and respond with either attractive or repulsive movements. The motility of growth cones is dependent on rapid reorganization of the actin cytoskeleton, presumably mediated by actin-associated proteins under the control of incoming guidance signals. This article reviews how one such family of proteins, the ADF/cofilins, are emerging as key regulators of growth cone actin dynamics. These proteins are essential for rapid actin turnover in a variety of different cell types. ADF/cofilins are heavily co-localized with actin in growth cones and are necessary for neurite outgrowth. ADF/cofilin activities are regulated through reversible phosphorylation by LIM kinases and slingshot phosphatases. LIM kinases are downstream effectors of the Rho GTPases Rho, Rac, and Cdc42. Growing evidence suggests that extracellular guidance cues may locally alter actin dynamics by regulating the activity of LIM kinase and ADF/cofilin phosphatases via the Rho GTPases. In this way, ADF/cofilins and their upstream effectors may be pivotal to our understanding of how guidance information is translated into physical alterations of the growth cone actin cytoskeleton. (J Histochem Cytochem 51:411420, 2003)
Key Words: neuronal pathfinding, growth cone, actin, ADF/cofilins, guidance cues
THE COMPLEX DEVELOPMENT of the nervous systems relies on precise targeting of neurons from the site of their origin to the cells they will eventually innervate. Neurons are highly polarized cells that are composed of a variety of dendritic arbors connected to a cell body via a single long axon. Axon elongation and dendritic branching occur by a process of highly polarized tip-directed growth, with expansion concentrated only in apical regions of the cell. At the distal ends of neurites are highly specialized structures called growth cones. In addition to being the site at which new materials are incorporated into the growing plasma membrane, growth cones determine the rate and direction of neurite outgrowth. Their high motility and their ability to reorganize rapidly in response to a variety of extracellular molecular cues enable them to guide the neuron to its final destination.
In recent years a myriad of guidance molecules have been identified (
The highly conserved family of actin-associated proteins, the actin depolymerizing factors (ADFs) and cofilins, are involved in regulating actin dynamics in the growth cone. Although ADFs and cofilin are products of different genes and differ quantitatively in their interactions with G- and F-actin (
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Actin Cytoskeletal Dynamics in the Growth Cone |
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The diverse functional roles of the actin cytoskeleton in the many cellular processes in which it is involved are made possible by the ability of actin filaments to form a variety of distinct assemblies with specific biophysical and biochemical properties. The formation of such assemblies is brought about by the interactions of actin monomers (G-actin) and filaments (F-actin) with a catalogue of actin binding proteins that serve to anchor, crosslink, or regulate the polymerization status of the actin network in the cell. Under physiological conditions, monomeric units reversibly polymerize into non-covalent filaments as ATP-bound actin (Fig 1). Shortly after incorporation of ATP-bound subunits into the filament, ATP is hydrolyzed to ADP-Pi-actin. The loss of inorganic phosphate is coupled to a change in the filament actin conformation (
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To understand how the interaction of growth cones with a guidance molecule can alter turning, it is first necessary to understand growth cone structure and cytoskeletal organization (Fig 2). The peripheral domain of the growth cone consists of a layer of flat web-shaped sheets of cytoplasm called lamellipodia, which surround the central domain of the growth cone. Finger-like protrusions called filopodia extend from the outer edge of the peripheral domain, connected to each other by lamellipodia (
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The mechanisms by which lamellipodia and filopodia extend and retract involve a number of actin binding proteins that are localized and regulated in specific regions of the leading edge of migrating cells. Examination of lamellipodia in keratocytes and fibroblasts by electron microscopy (
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The assembly of actin filaments is believed to result from a combination of nucleation, polymerization, and annealing of short filaments, although which of these processes predominates in growth cones remains unclear. Actin elongation in this region generates the force necessary to drive lamellipodial and filopodial extension. Filament assembly may be brought about by nucleation factors such as the Arp2/3 complex (
AC proteins may also contribute to nucleation by severing growing actin filaments, thereby generating new filament ends. Whether AC proteins promote filament assembly or disassembly depends on a number of different factors. For example, if the filaments were capped or tethered at the pointed ends, dissociation of monomers would be prevented, allowing net filament assembly to occur from the barbed ends.
After assembly at the leading edge, bundles of actin move back to the central domain of the growth cone via myosin-mediated retrograde F-actin flow (
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Regulation of Actin Dynamics by ADF/Cofilin in the Growth Cone |
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Several lines of evidence point towards AC as a crucial protein in growth cone motility. This section focuses on how the unique activities of AC may serve to mediate the rapid changes in actin dynamics observed in growth cones. The depolymerizing activity of ACs arises from their ability to increase the rate of dissociation of ADP-actin from the pointed end of actin filaments (
Animal ACs are regulated by phosphorylation on a highly conserved serine residue (
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In addition to biochemical studies, in vivo observations have confirmed the importance of AC in neuronal development. ADF is expressed at high levels in neurons and co-localizes with F-actin in growth cones (
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Rho GTPase Regulation of Neuronal Morphology |
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The Rho family of small GTPases (Rho, Rac, and Cdc42) activate various pathways that affect cell locomotion through dynamic regulation of the actin cytoskeleton. The activities of the Rho GTPases were first characterized by microinjection studies in fibroblasts. For example, Rho A stimulates the formation of stress fibers (
More recent findings also support the involvement of Rac and Cdc42 in growth cone protrusion. For example, constitutively active Rac and Cdc42 increase dendritic branching in Xenopus (
Other studies further investigated the role of small GTPases in growth cone collapse (
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Rho GTPase Signaling to ADF/Cofilin in the Growth Cone |
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It is clear that the effects of Rho GTPases on growth cone morphology and motility require their signaling to specific actin-modulating proteins. At present, only one group of such proteins, the ADF/cofilins, appears to possess the necessary upstream effectors to account for the Rho GTPase-triggered actin reorganization observed in neuronal and non-neuronal cells. The kinases regulating AC in vertebrates are LIM kinase (LIMK) (
Both LIMK1 and LIMK2 are downstream effectors of the Rho GTPases (Fig 4, steps 614). LIMK1 and LIMK2 are regulated by Rac, Cdc42, and Rho (
The few studies that have sought to address the link between Rho GTPases and AC proteins in neurons have yielded some interesting results. LIMKs contain two amino-terminal LIM domains, a central PDZ domain, and a carboxyl-terminal kinase domain with serine/threonine kinase activity. Overexpression of the non-catalytic N-terminal domains of LIMK1 decreased neurite extension after stimulation with NGF and Rho-kinase inhibitor but had no effect on spontaneous neurite outgrowth (
Other studies have shown that the phosphorylation state of AC in neurons is influenced by growth factors as well as elements of second messenger systems. Elevations in intracellular calcium and cAMP levels bring about extensive dephosphorylation of ADF in cortical neurons (
It is important to note that net AC dephosphorylation is not always necessary for growth factor-induced lamellipodial and filopodial extension. When fibroblasts were treated with EGF, rapid lamellipodial growth was observed () of 14-3-3 protein shielding its dephosphorylation from general phosphatases (
Although the AC phosphorylation pathway occurs through Rho activation of LIMK1, the regulation of the dephosphorylation is less well understood. Recently, an ADF/cofilin phosphatase called slingshot was identified (
Only one study has shown how signaling from an extracellular guidance cue can directly influence the behavior of AC proteins in neurons.
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Conclusion |
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The evidence presented in this review clearly defines AC proteins as essential regulators of neuronal growth cone actin dynamics. The current models for actin-based cell motility all require fast turnover of actin filaments at the leading edge. The unique ability of AC proteins to increase the rate of monomer dissociation from filaments may, in conjunction with other actin-associated proteins, drive the rapid actin filament dynamics observed in neuronal growth cones and other migrating cells. Actin reorganization in growth cones appears to be controlled by the Rho GTPases, which function downstream of at least some attractive or repulsive extracellular guidance molecules. There is now a definitive link between signaling from one guidance cue to AC proteins. AC regulation by phosphorylation appears to be a crucial way in which these proteins are regulated. AC functioning in growth cones is dependent on a balancing of kinase and phosphatase pathways. The recent identification of the slingshot family of AC phosphatases warrants the identification and localization of their neuronal isoforms. This would allow the effect of partial loss- and gain-of-function mutants of AC phosphatase on the growth cone actin cytoskeleton to be assessed, as well as to determine the mechanism of slingshot regulation. Subsequent studies could then focus on how the combined activities of AC phosphatase and LIM kinase mediate the changes in growth cone motility stimulated by guidance molecules. Turning responses result from the asymmetric collapse of the growth cone, a change associated with the assembly and disassembly of actin-based structures. It seems likely that these changes will involve the spatially coordinated regulation of AC proteins.
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Footnotes |
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1 Presented as part of the Cytoskeletal Dynamics and Path Finding of Neuronal Growth Cones Symposium, 6th Joint Meeting of the Japan Society of Histochemistry and Cytochemistry and the Histochemical Society, University of Washington, Seattle, WA, July 1821, 2002.
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Acknowledgments |
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Supported in part by grants from the Alzheimer's Association (IIRG-01-2730) and the National Institutes of Health (GM35126, NS40371) to JRB.
Received for publication September 16, 2002; accepted October 26, 2002.
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