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Letourneau P (2009) Axonal Pathfinding: Extracellular Matrix Role. In: Squire LR (ed.) Encyclopedia of Neuroscience, volume 1, pp. 1139-1145. Oxford: Academic Press.
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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
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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
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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 aggregates, and by the establishment of adhesions to stabilize these and basal laminae, which are discrete ECM layers protrusions and promote the advance of microtubules. at tissue interfaces. One major adhesive interaction of growth cones involves binding of integrin recep- Cadherins and IgCAMs Stimulation of N-cadherin tors to adhesive ECM proteins, especially the laminins. and IgCAMs, such as NCAM and L1, by ligand bind- Two other major adhesive interactions involve growth ing between cells leads to activation of the FGF recep- cone contacts with cells or other axons along their tor tyrosine kinase, which triggers signals involving 2 pathways. These interactions involve two groups of PLC-gamma, DAG lipase, cytoplasmic [Ca þ] eleva- adhesive molecules, the cadherins and the immuno- tion, and activation of MAPK. IgCAMs also signal globulin superfamily of cell adhesion molecules via Src kinases to activate Rac1, PI3K, and MAPK. (IgCAMs). Cadherins are expressed on all tissue Cadherin signaling is also reported to activate Rac1. types, including neurons and axons. Cadherin adhe- Thus, several pathways activated by cadherins and sions involve homophilic binding between like cad- IgCAMs promote actin filament polymerization. herin molecules on two interacting cells. Weaker Adhesive binding of cadherins and IgCAMs provides heterophilic interactions between different cadherins anchorage for actin filaments, creating the clutch can also occur. IgCAMs are also expressed on all necessary for growth cone migration. The cytoplas- tissues, including neurons. Adhesive interactions of mic tails of many cadherins, such as N-cadherin,
IgCAMs can involve homophilic interactions, similar bind catenins, which bind actin filaments and link to cadherins, but also heterophilic interactions in N-cadherin adhesive sites to the actin cytoskeleton which an IgCAM on a growth cone binds a different in growth cones (Figure 4). The cytoplasmic domain IgCAM on adjacent cells. Even heterophilic inter- of L1 binds the cytoskeletal linker ankyrin, but L1– actions of IgCAMs with non-IgCAMs occur. ankyrin interactions are involved in stable adhesive junctions, such as at nodes of Ranvier, and not in Integrin adhesion receptors Integrin receptors are growth cone migration. Members of the ezrin– heterodimers of alpha and beta subunits. More than moesin–radixin (ERM) proteins mediate actin fila- 20 integrin heterodimers have been identified in ment binding to membranes, and interactions of L1 humans. The binding specificity for ECM compo- (and other IgCAMs) with ERM proteins may serve as nents depends on the particular combination of alpha a clutch in growth cone protrusions that bind via L1 and beta subunits in a heterodimer. The 12 integrin or other IgCAMs. dimers that are expressed in the mammalian ner- These adhesion receptors can be regulated in ways vous system include receptors for collagens, laminin-1 that are important to growth cone pathfinding. The and laminin-5, fibronectin, tenascin, thrombospondin, expression levels of integrin receptors on growth vitronectin, and VCAM-1. A growth cone can express cones are increased when laminin levels are low or multiple integrins, allowing interactions with multiple when ECM proteins, such as proteoglycans, which
ECM molecules. The cytoplasmic domains of integrins interfere with laminin–integrin binding, are present. lack enzymatic activities, but when integrins bind adhe- These responses would maintain growth cone adhe- sive ligands, conformational shifts in the cytoplasmic sion and migration in environments when access to domains trigger formation of focal contacts that laminin is reduced. L1 is endocytosed from central involve integrin clustering and creation of docking regions and recycled to the leading margin of growth sites for proteins that initiate signaling and links to cones, increasing availability of L1 for adhesive con- the cytoskeleton. When lamellipodia and filopodia of tacts of lamellipodia and filopodia. The functions growth cones bind laminin-1, proteins that localize to of adhesion receptors can also be modulated from the contact sites include paxillin, talin, vinculin, zyxin, the cytoplasm in an ‘inside-out’ manner or via cis and focal adhesion kinase (FAK). Vinculin and talin interactions with other components of the plasma link actin filaments to the adhesive contacts, providing membrane. An important manner in which guidance
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1142 Axonal Pathfinding: Extracellular Matrix Role
Collagen
PIP Integrin 2 b a Arp2/3 PIPKI complex Vinculin g
Talin
P FAK
Actin
Figure 3 A model of integrin binding to ECM molecules and the formation of intracellular adhesive complexes. An alpha–beta integrin heterodimer is shown bound to a collagen fibril, and the intracellular adhesion complex is pictured, showing the proteins vinculin and talin, which are involved in linkage to actin filaments, and FAK kinase, which initiates signaling cascades. The Arp2/3 complex nucleates actin filament assembly. Reproduced from Brakebusch C and Fa¨ssler R (2003) The integrin–actin connection, an eternal love affair. EMBO Journal 22: 2324–2333, with permission from Nature Publishing Group.
molecules exert their positive and negative effects on The first growth cones that ‘pioneer’ a pathway growth cone pathfinding is by modulating the func- have limited options for binding to ECM or cell sur- tions ofadhesive receptors (Figure 2). For example, the face adhesion molecules on adjacent cells, whereas negative cue semaphorin 3A may inhibit growth cone growth cones that enter an established pathway can migration by blocking integrin-mediated cell adhesion. track along previously extended axons by binding to
In addition, adhesion mediated by N-cadherin is cadherins and IgCAMs expressed on the surfaces of inhibited by the negative guidance cue Slit protein via axonal shafts. Several in vivo examples of pathfinding its receptor, Robo. Thus, the negative or repulsive roles of adhesion molecules are described in the fol- effects of semaphorin 3A and Slit on growth cone lowing sections. pathfinding can involve these inhibitory effects on growthcone adhesion. On the other hand, the attrac- Laminins tant netrin signals to activate the kinase FAK, which promotes integrin-mediated adhesion, suggesting that Laminins are large adhesive glycoproteins (MW positive guidance cues activate adhesive interactions of 1 000 000 Da) that consist of heterotrimers of alpha, growthcones. beta, and gamma chains. Ten laminin chains are known, forming 11 known heterotrimers with widely
Adhesion Molecules and Growth varied expression throughout different tissues. The laminins present several domains that mediate laminin Cone Pathfinding binding to several cell surface receptors and to other What are the roles of these adhesion molecules in the ECM components. The most common laminins are pathfinding behaviors of growth cones? Major path- typically present in basal laminae, an ultrastructural ways that are followed by many growing axons offer ECM layer associated with epithelia, muscle cells, multiple adhesive ligands for growth cone migration, Schwann cells, and glia. Laminin-1, which has been such as laminins, fibronectin and collagens in the studied the most, promotes axonal growth in vitro
ECM, and cadherins and IgCAMs on adjacent cells from virtually every type of neuron, indicating that and axons. These multiple options for adhesion may laminins have broad roles in promoting growth cone provide redundancy, ensuring growth cones form migration. Examples of growth cone migration along sufficient adhesive contacts for effective migration. basal laminae include growth cones of Rohon–Beard
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Axonal Pathfinding: Extracellular Matrix Role 1143
expression of laminin diminishes during development,
although laminin remains present in basal laminae. In view of the wide distribution of laminins and the ability of laminin-1 to promote robust axonal growth
from many neuronal types, it is thought that laminins function permissively, providing adhesion that is required for growth cone migration, but not in an
instructive manner to influence pathfinding decisions. Laminins and other ECM molecules may broadly promote growth cone migration along a pathway, whose boundaries are defined not by the absence of
adhesive ECM molecules but, rather, by the expres- sion in adjacent tissues of negative guidance cues, such as slits or semaphorins. This ‘surround repul- b Catenins sion’ occurs in both developing CNS and PNS. Sev- a eral mutational studies have reported specific errors Actin in pathfinding when a laminin is absent or blocked. filament Laminin function is essential for growth cone turning in the grasshopper limb bud, and zebra fish with mutations in the laminin-alpha-1 chain exhibit multi- Other ple axon guidance defects throughout the CNS, actin-binding proteins but not in every location. These results suggest that Actin laminin-mediated adhesion is essential for growth monomer cone navigation in at least some instances.
Figure 4 A model of homophilic adhesion between cadherin adhesion molecules and the intracellular binding to actin fila- Fibronectin ments. Cadherin molecules bind between cells and become linked to actin filaments by way of interactions with alpha and beta Fibronectin is a large adhesive glycoprotein (MW catenins. From Weis WI and Nelson WJ (2006) Re-solving the 250 000 Da) that is widely distributed in the ECM, cadherin–catenin–actin conundrum. Journal of Biological Chem- including within ganglia and the endoneurium of istry 281: 35593–35597. the PNS. Like the laminins, the fibronectin molecule contains multiple domains that mediate binding to other ECM components and to multiple cellular neurons in Xenopus, growth cones of retinal ganglion cells in the retina and optic nerve, and pioneer axons in receptors, including several integrin heterodimers. the grasshopper limb bud. However, in addition to During development of the PNS and CNS, fibronectin is present in a punctate distribution in loose cellular basal laminae, laminin is transiently expressed in the loose cellular environments of developing tissues, spaces of immature nervous tissue, and eventually fibronectin expression diminishes as development including the nervous system, on cell surfaces and associated with sparse ECM fibers. The growth cones ends, especially in the CNS. In tissue culture studies, fibronectin promotes axonal growth, but not as vig- that pioneer pathways, such as the corticofugal path- way of the neocortex or the medial longitudinal fascic- orously as does laminin. In addition, axonal growth ulus from the brain into the spinal cord, migrate within by PNS neurons on fibronectin surfaces exceeds the responses of CNS neurons, probably because PNS loose extracellular spaces in the wall of the immature central nervous system (CNS), where the cells are neurons express higher levels of fibronectin receptors labeled in a punctate manner by laminin antibodies. than CNS neurons. Evidence is lacking for a require- ment for fibronectin in growth cone pathfinding. The expression of laminin on these cells is transient, and eventually laminin immunoreactivity is restricted Integrins to the basal lamina at the outer boundary of the CNS wall. In the developing peripheral nervous system Because neurons express multiple integrin subunits (PNS), laminin is expressed in basal laminae and at and because many ECM components, such as colla- early stages in the mesenchyme through which motor gen, laminin, or fibronectin, can bind more than one and sensory axons extend. Schwann cells express abun- integrin heterodimer, the essential roles of particular dant laminin, forming the basal laminae that enclose integrins in growth cone pathfinding are not clearly axon–Schwann cell units. This punctate cellular defined. Mouse knockouts of a1 and a6 integrins,
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1144 Axonal Pathfinding: Extracellular Matrix Role which are laminin-1 receptors, do not reveal clear includes a large number of molecules, which have defects, however, injections of anti-b1 integrin, part functions in axonal pathfinding not only as cell adhe- of several neuronal receptors for ECM proteins, into sion molecules but also as axonal guidance cues and Xenopus embryos disrupts retinal axonal pathfind- as receptors of guidance cues. This discussion is ing. Similarly, conditional knockout of b1 integrin in restricted to two members of this large family, L1 sensory neurons results in deficits in innervation of and NCAM. The IgCAM L1 is widely expressed on skin, where sensory axons extend through the dermal axons in the developing CNS and PNS, and tissue
ECM and along the epidermal basal lamina. The a4ß1 culture studies show that substrates coated with L1 integrin heterodimer is specifically implicated in the promote homophilic adhesion and axonal growth growthand arborization of sympathetic axons within from many neuronal types. Spontaneous human cardiacmuscle. In Drosophila, mutations in the integ- mutations in the L1 gene and mouse L1 knockout rins a-PS1 and-PS2 lead to pathfinding errors. studies both indicate important roles for L1 in brain development and function. Multiple anatomical and Cadherins functional deficits result from human and mouse L1
Cadherins are characterized as single-pass transmem- mutations, including a failure of corticospinal axons brane proteins that contain an ectodomain of five to decussate in the hindbrain pyramids. Crossing cadherin repeats and a conserved cytoplasmic tail. defects were not found in other tracts or were not so
Binding of calcium ion stabilizes an extended rodlike extensive. L1 also interacts in cis with receptors for structure of the ectodomain, which is necessary for other guidance cues, including the semaphorin 3A optimal adhesion by alignment of cadherin molecules receptor, suggesting that the defect in pyramidal on apposing cells. There are at least 100 cadherins, decussation observed in L1 mutants could be due to and most are expressed in the developing vertebrate disrupted pathfinding responses to semaphorin 3A brain on immature cells, neurons, and glia. Their and other guidance cues, as well as to reduced growth functions are numerous, including cell sorting, bound- cone tracking along axons. ary formation, target recognition, synaptogenesis, and Another prominent neuronal IgCAM is NCAM, synapse function. Regarding axonal pathfinding, the the first neuronal IgCAM identified. NCAM is widely widely expressed N-cadherin stimulates in vitro axonal expressed on immature neurons and glia and also on growth from a variety of CNS and PNS neurons. other embryonic cells, such as myoblasts. In tissue In vivo studies involving antibody injection or genetic culture studies, NCAM mediates neuronal adhesion mutation also implicate N-cadherin in axon growth and axon growth. In addition to homophilic adhesive and fasciculation. These results indicate that cadherins interactions, NCAM also forms heterophilic adhe- promote growth cone migration along axons in highly sive interactions. Antibodies against NCAM can populated common pathways, but it is unclear whether induce axon defasciculation in vitro and in vivo. Sev- cadherins play a role in the pathfinding of early pioneer eral isoforms of NCAM are expressed, and in some growthcones. In some cases, a common pathway may situations NCAM carries a carbohydrate polysialic be shared by several classes of elongating axons, which acid (PSA) moiety that reduces NCAM adhesion. are distinguished by the expression of different cadher- In NCAM-deficient mice defects in fasciculation of ins. For example, the tectofugal projections of chickens hippocampal axons were observed, but in general express four different cadherins among different axon only minor defects in development or behavior were fascicles. These cadherins may mediate specific path- observed. Perhaps, in the absence of NCAM, other finding, as the formation of homophilic adhesions of cell adhesion molecules serve the same functions. growth cones to axons expressing the same cadherin directs growth cones along specific axon fascicles Adhesion Molecules and Axonal toward their targets. Forced expression of specific cad- Regeneration herins causes growth cones to abnormally follow fas- cicles that express the same cadherin. Finally, growth When the pathfinding phase of circuit construction cones often share expression of specific cadherins with ends, as growth cones reach their targets, the expres- neurons in their particular target. Thus, cadherins sion of neural cell adhesion molecules and their recep- also have roles in target recognition and subsequent tors is downregulated. However, injury or damage to synaptogenesis. nervous tissues can disconnect neural circuits, and axons must regenerate in order to reconnect neurons. L1 and NCAM IgCAMs When axons are injured in the PNS, axon regeneration Proteins that contain an immunoglobulin (Ig)-like is often robust, leading to varying degrees of func- domain constitute the Ig superfamily, which makes tional recovery. Schwann cells, which ensheath all up more than 2% of human genes, constituting the PNS axons, stimulate axonal regeneration by upregu- largest gene family. The neuronal Ig superfamily lating their expression of growth factors, and
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Axonal Pathfinding: Extracellular Matrix Role 1145 laminins, fibronectin, and cadherin, as substrates for growth cone migration during development contain growth cones. Axon regeneration in the PNS is also one or, perhaps more typically, multiple adhesive promoted by increased expression of integrin recep- ligands available to growth cones. The navigational tors by regenerating neurons. In the CNS of adult decisions of growth cone pathfinding are based on mammals, regeneration of injured axons is poor, local differences in adhesive stability for growth and recent research has focused on inhibitory compo- cone protrusions and in dynamic protrusive activity, nents of myelin and glial scars that block growth cone as based on adhesive signaling and the integration of adhesion and trigger signals that inhibit growth cone signaling triggered from other guidance cues. motility. In lower vertebrates, CNS regeneration is often successful, and this involves the upregulation See also: Axon Guidance: Morphogens as Chemoattrac- of expression of adhesive ligands, such as L1 and tants and Chemorepellants; Axon Guidance: Building cadherins, as demonstrated in regenerating zebra Pathways with Molecular Cues in Vertebrate Sensory fish optic nerves and spinal cords. Systems; Axon Guidance: Guidance Cues and Guidepost Several strategies for improving axonal regenera- Cells; Axonal Pathfinding: Netrins; Axonal Pathfinding: tion in mammalian model systems, and eventually Guidance Activities of Sonic Hedgehog (Shh); Growth humans,emphasize measures to improve the adhesive Cones; Semaphorins. environment for growth cone migration. When stem cells that express L1 are transplanted into a mamma- lian CNS lesion, increased regeneration of cortico- Further Reading spinal axons occurs. Purkinje cells transfected to express L1 and GAP43 show enhanced axonal regen- Brakebusch C and Fa¨ssler R (2003) The integrin–actin connection,
an eternal love affair. EMBO Journal 22: 2324–2333. eration. In vitro regeneration of axons by adult neu- rons on laminin and fibronectin is improved by Clegg DO, Wingerd KL, Hikita ST, and Tolhurst EC (2003) Integrins in the development, function and dysfunction of the transfection of neurons to express increased levels of nervous system. Frontiers in Bioscience 8: d723–d750. the appropriate a integrin chains. Finally, many natu- Colognato H, French-Constant C, and Feltri ML (2005) Human ral and synthetic bridges have been designed that diseases reveal novel roles for neural laminins. Transactions in include adhesion molecules to promote axonal regen- Neuroscience 28: 480–486. eration across lesion sites. These studies demonstrate Dent EW and Gertler FB (2003) Cytoskeletal dynamics and trans- port in growth cone motility and axon guidance. Neuron 40: that strategies to increase the adhesive interactions of 209–227. regenerating growth cones can stimulate axonal regen- Gordon-Weeks PR (2000) Neuronal Growth Cones. Cambridge, eration after injuries in adults. Probably, improved UK: Cambridge University Press.
Hortsch M (2003) Neural cell adhesion molecules – brain glue and axonal regeneration in adults will also require an increase in the intrinsic ability of adult neurons to much more! Frontiers in Bioscience 8: d357–d359. Huber AB, Kolodkin AL, Ginty DD, and Cloutier JF (2003) Signal- sprout and grow axons. This may involve upregulation ing at the growth cone: Ligand–receptor complexes and the of genes for adhesion receptors, for other guidance cue control of axon growth and guidance. Annual Review of Neu- receptors, and for proteins that drive the dynamic roscience 28: 509–563. cytoskeletal functions of immature neurons. Hynes RO (2002) Integrins. Bidirectional, allosteric signaling machines. Cell 110: 673–687. Kamiguchi H (2003) The mechanism of axon growth: What we Summary have learned from the cell adhesion molecule L1. Molecular Neurobiology 28: 219–228. Growth cone adhesion is integral to the mechanism of Kiryusho D, Berezin V, and Bock E (2004) Regulators of neurite
outgrowth: Role of cell adhesion molecules. Annals of the growth cone migration and pathfinding. Adhesive interactions of growth cones provide stability for New York Academy of Sciences 1014: 140–154. Redies C, Treubert-Zimmermann U, and Luo J (2003) Cadherins as lamellipodial and filopodial protrusions of growth regulators for the emergence of neural nets from embryonic cones and also act as signaling centers that regulate divisions. Journal of Physiology (Paris) 97: 5–15. actin and microtubule dynamics and organization in Sakisaka T and Takai Y (2005) Cell adhesion molecules in the CNS. a migrating growth cone. The adhesive interactions Journal of Cell Science 118: 5407–5410. of growth cones are also a target of guidance cues Suter DM and Forscher P (2000) Substrate–cytoskeletal coupling as a mechanism for regulation of growth cone motility and guid- that determine where growth cones turn, branch, and ance. Journal of Neurobiology 44: 97–113. stop migrating. Migrating growth cones make three Thiery JP (2003) Cell adhesion in development: A complex signal- kinds of adhesive contacts with ECM and with other ing network. Current Opinion in Genetics & Development 13:
365–371. cells. These contacts involve integrin receptors, which recognize laminin and other ECM components; Weis WI and Nelson WJ (2006) Re-solving the cadherin–catenin– actin conundrum. Journal of Biological Chemistry 281: 35593– cadherins, which form homophilic adhesions; and 35597. IgCAMs, which can form homophilic and hetero- Wen Z and Zheng JQ (2006) Directional guidance of nerve growth philic adhesive interactions. Major pathways of cones. Current Opinion in Neurobiology 16: 52–58.
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