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Letourneau, P This article was originally published in the Encyclopedia of Neuroscience published by Elsevier, and the attached copy is provided by Elsevier for the author's benefit and for the benefit of the author's institution, for non- commercial research and educational use including without limitation use in instruction at your institution, sending it to specific colleagues who you know, and providing a copy to your institution’s administrator. All other uses, reproduction and distribution, including without limitation commercial reprints, selling or licensing copies or access, or posting on open internet sites, your personal or institution’s website or repository, are prohibited. For exceptions, permission may be sought for such use through Elsevier's permissions site at: http://www.elsevier.com/locate/permissionusematerial Letourneau P (2009) Axonal Pathfinding: Extracellular Matrix Role. In: Squire LR (ed.) Encyclopedia of Neuroscience, volume 1, pp. 1139-1145. Oxford: Academic Press. Author's personal copy Axonal Pathfinding: Extracellular Matrix Role 1139 Axonal Pathfinding: Extracellular Matrix Role P Letourneau , University of Minnesota, Minneapolis, ‘pioneering’ microtubules. These dynamic micro- MN, USA tubules project forward into an actin filament net- work that fills flattened dynamic projections, called ã 2009 Elsevier Ltd. All rights reserved. lamellipodia, and fingerlike filopodia. This extensive filament system is continually remodeled, as actin filaments initiate and polymerize at the front margin Introduction and are then moved back to be fragmented and de- Normal behavior and other neural activities depend polymerized, recycling subunits to the front. Multiple actin-binding proteins regulate this dynamic organi- on the correct wiring of neural circuits during devel- opment. A critical step in forming neural circuits is zation of actin filaments. the growth of axons from nerve cell bodies to the sites Growth cone migration is driven by forces produced where synaptic connections are made. In spanning within this actin filament domain. Actin polymeriza- tion creates protrusive forces that expand lamellipodia between neural somata and their synaptic targets, growing axons forge pathways that become the axonal and elongate the tips of filopodia. Myosin motor mol- tracts and peripheral nerves of the mature nervous ecules bind actin filaments and generate mechanical forces that move cargo bound to the myosin tail system. The routes that axons take to reach their tar- gets are determined by motile activities at their tips, domains or pull on actin filaments to create tensions. called growth cones. Growth cones extend fine protru- Myosin II motor activity pulls actin filaments rear- ward, where they are depolymerized. Tensions gener- sions that adhere to nearby cells and surfaces. These adhesive contacts provide a toehold from which fur- ated by myosin II activity in the actin-rich leading ther protrusions are made. As growth cones crawl margin can either direct or halt microtubule advance, forward, they choose a path by detecting and respond- depending on the situation. Myosin II-generated ten- sions produce the exploratory movements of lamelli- ing to the spatial and temporal distributions of extra- cellular guidance molecules encountered in their local podia and filopodia, whereas excessive levels of environments. Five major families of extracellular tension may sweep microtubules back in a contracting actin network that can collapse a growth cone. It is in molecules – netrins, neurotrophins, semaphorins, slits, and ephrins – provide positive and negative cues the context of these dynamic cytoskeletal activities that that orient the migration of growth cones to their adhesive interactions are critical to growth cone migra- tion (Figure 2). targets. These guidance molecules bind receptor pro- teins on growth cones and initiate cytoplasmic signals Adhesive Contacts of Growth Cones that regulate the motility and adhesive contacts that Growth cone plasma membranes contain adhesion determine the advance, retreat, turning, branching, and stopping of growth cones. This article describes receptors that bind noncovalently to adhesion mol- molecules that play a key role in axonal pathfinding by ecules on other cells or surfaces. Lamellipodia and mediating the adhesive interactions necessary for filopodia initiate adhesive interactions as they explore growth cone migration. their environment, and if these bonds persist, recep- tors cluster to form discrete adhesive contacts, which include intracellular adhesion complexes. Adhesion Mechanism of Growth Cone Migration complexes remain in place or shift rearward as a growth cone advances. These adhesive complexes Cytoskeletal Dynamics play two roles in growth cone migration. First, they Growth cone migration and axonal elongation include proteins that anchor actin filaments at adhe- involve the cytoskeletal components, microtubules sive sites. These links constitute a ‘clutch’ that stops and actin filaments. Axon elongation requires the the retrograde movement of actin filaments and per- advance and polymerization of microtubules, which mits the advance of microtubules and axonal orga- are bundled in the axon but which spread apart in the nelles (Figure 2). Without stabilization provided by growth cone, where individual microtubules dynami- adhesive contacts growth cone migration fails, and cally probe forward to the front of a growth cone via tensions within the axonal cytoskeleton cause axonal polymerization and movement involving microtubule retraction. Second, these complexes include proteins motor molecules (Figure 1). Axonal growth occurs of signaling cascades, protein kinases, protein phos- where the main microtubule bundle and associated phatases, and Rho GTPases, which act on proteins organelles advance in the growth cone, as determined that regulate the organization of actin filaments and by the positions and stabilization of these forward microtubules. Thus, adhesive contacts provide points Encyclopedia of Neuroscience (2009), vol. 1, pp. 1139-1145 Author's personal copy 1140 Axonal Pathfinding: Extracellular Matrix Role Figure 1 The distribution of microtubules and actin filaments in developing neurons and in axonal growth cones. Microtubules (green) are densely packed in the neuronal cell bodies (S) and are bundled in the axons and branches. Actin filaments are arrayed in filament networks and bundles in the peripheral domains (P) of the growth cones and along the shafts of the axons, where small areas of actin filament dynamics may give rise to collateral branches (B). In a growth cone, the microtubules from the central bundle of the central domain (C) splay apart and individual microtubules extend into the P domain and into filopodia (arrows). Leading edge protrusion Myosin II Actin polymerization Retrograde Clutch (stop retrograde flow) Advance of microtubules and organelles Myosin II flow of actin Cell adhesion receptor Attractive cue Repulsive cue Figure 2 A model of the mechanism of growth cone migration. Actin polymerization pushes the leading margin of the growth cone forward. Forces generated by myosin II pull actin filaments backwards, where filaments are disassembled. When growth cone receptors make adhesive contacts with a surface, a ‘clutch’ links the adhesive contact to actin filaments of the leading edge, and the retrograde flow of actin filaments stops. This permits the advance of microtubules and organelles and promotes axonal elongation. Intracellular signaling generated by attractive and repulsive axonal guidance cues interacts with the molecular mechanisms of actin polymerization, myosin II force generation, adhesive contacts, and microtubule advance to regulate the paths of growth cone migration. of stability that are essential to growth cone migra- cones of neurons of a particular type. Extracellular tion, and they are signaling centers from which regu- positive and negative axonal guidance cues, whether latory activities promote growth cone motility. surface bound or soluble, signal through their recep- The genetic regulation that determines neuronal tors to modulate an interacting set of pathways that phenotype also directs expression of receptors for regulate cytoskeletal and membrane dynamics. Thus, adhesive ligands and guidance cues by the growth growth cone behaviors reflect a complex integration Encyclopedia of Neuroscience (2009), vol. 1, pp. 1139-1145 Author's personal copy Axonal Pathfinding: Extracellular Matrix Role 1141 of signaling events triggered at multiple receptors for a clutch for growth cone migration (Figure 3). The guidance cues and adhesion molecules. By locally presence of the adapter protein paxillin and activation regulating the interplay of adhesive contacts and of FAK initiates further protein interactions and signal- cytoskeletal dynamics within a growth cone, guid- ing by Src family kinases, MAP kinases, and Rho ance cues determine the pathways of axonal growth GTPases. Activation of Rac1 and Cdc42 GTPases pro- (Figure 2). motes actin polymerization by regulating actin-binding Three major types of adhesive interactions pro- proteins and actin filament dynamics. Thus, when mote growth cone navigation. Growth cones migrate integrins on growth cones bind laminin-1, growth within extracellular spaces that contain a complex cone migration is stimulated by increased actin fila- mixtureof glycoproteins, organized into an extra- ment polymerization to protrude the leading margin cellular matrix (ECM) of fibers, protein
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