Subcellular Patterning: Axonal Domains with Specialized Structure and Function
2015; Elsevier BV; Volume: 32; Issue: 4 Linguagem: Inglês
10.1016/j.devcel.2015.01.017
ISSN1878-1551
AutoresElizabeth A. Normand, Matthew N. Rasband,
Tópico(s)Nerve injury and regeneration
ResumoMyelinated axons are patterned into discrete and often-repeating domains responsible for the efficient and rapid transmission of electrical signals. These domains include nodes of Ranvier and axon initial segments. Disruption of axonal patterning leads to nervous system dysfunction. In this review, we introduce the concept of subcellular patterning as applied to axons and discuss how these patterning events depend on both intrinsic, cytoskeletal mechanisms and extrinsic, myelinating glia-dependent mechanisms. Myelinated axons are patterned into discrete and often-repeating domains responsible for the efficient and rapid transmission of electrical signals. These domains include nodes of Ranvier and axon initial segments. Disruption of axonal patterning leads to nervous system dysfunction. In this review, we introduce the concept of subcellular patterning as applied to axons and discuss how these patterning events depend on both intrinsic, cytoskeletal mechanisms and extrinsic, myelinating glia-dependent mechanisms. Patterning is how organisms become segregated into spatially and functionally distinct structures or domains. Patterning is a common process among multicellular organisms as diverse as plants, invertebrates, and vertebrates. Early in development, patterning sets up broad domain distinctions. One of the earliest patterning events determines animal versus vegetal poles, which form the organism or support tissues like the yolk sac, respectively. Soon after, in the gastrulation stage, endoderm, ectoderm, and mesoderm germ layers become differentiated, and the body axes are established. As development proceeds, patterning events establish finer and finer degrees of specialization. For example, within the nervous system, different brain regions have distinct neuronal subtypes and cytoarchitectures and extend long-range axonal projections to highly specific and often unique target regions. An example of this is the patterning of the neocortex into discrete layers, each of which contains a characteristic array of neurons that receive inputs from and project to distinct cell types, have unique developmental origins, and express unique sets of genes and proteins. Overall, these features are established during development by an exquisite interplay of cell-intrinsic and cell-extrinsic signals. Here we extend the concept of patterning from regional specification and cell fate induction to patterning of subcellular domains. Traditional patterning emphasizes the differentiation and specialization of cells and groups of cells. In contrast, subcellular patterning is the segregation of spatially distinct, highly organized, and functionally specialized protein complexes within a cell. These processes have also been referred to as compartmentalization and/or subcellular polarization. Exquisite control over the expression, trafficking, and interactions of these protein complexes is required to target and maintain them in their correct subcellular locations at the right time. In this review, we focus on subcellular patterning events in axons. We emphasize myelinated axons because they are highly polarized with many spatially, structurally, and functionally distinct protein complexes whose formation and positioning are critical for proper nervous system function. As with more traditional patterning mechanisms that depend on interactions between and among cells, patterning of myelinated axons depends on interactions between neurons and glia. Axons are patterned into repeating excitable and non-excitable domains for the efficient and rapid transmission of electrical signals. These excitable domains include the axon initial segment (AIS) and nodes of Ranvier, and their disruption by disease or injury severely impairs nervous system function. The AIS, located at the interface between the neuronal cell body and axon (Figure 1A), integrates synaptic inputs to generate an action potential. Its position and proximity to the cell body is determined by both activity and cell type. The axon transmits the action potential over very long distances without diminution of speed or amplitude while minimizing the energy used to propagate the action potential. To do this, axons are wrapped by myelin, which is made by oligodendrocytes and Schwann cells in the CNS and peripheral nervous system (PNS), respectively. Myelin decreases membrane capacitance and increases membrane resistance to minimize the dissipation of ionic current as the action potential propagates along the axon. Gaps in the myelin sheath, called nodes of Ranvier, are located at regular intervals to regenerate the action potential (Figures 1B–1D). The spacing, or patterning, of nodes along the axon influences the speed of action potential propagation (Court et al., 2004Court F.A. Sherman D.L. Pratt T. Garry E.M. Ribchester R.R. Cottrell D.F. Fleetwood-Walker S.M. Brophy P.J. Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves.Nature. 2004; 431: 191-195Crossref PubMed Scopus (175) Google Scholar). The AIS and nodes of Ranvier consist of a common set of ion channels, cell adhesion molecules, and cytoskeletal scaffolds, but there are differences in the way these molecules are organized along the axon. In this review, we use nodes of Ranvier and the AIS as representative examples of subcellular patterning. We emphasize the interplay of cell-intrinsic and cell-extrinsic mechanisms that work together to pattern the axon. Finally, we discuss some examples of diseases or injuries that disrupt nodes and the AIS and altered axonal physiology. Nodes of Ranvier are ∼1-μm-long axonal Na+ channel clusters that occur at gaps in the myelin sheath and regenerate action potentials (Figures 1B–1D; (3) in Figure 2). Nodes of Ranvier and the AIS share a common core protein composition that includes voltage-gated ion channels, the cell adhesion molecules (CAMs) neurofascin 186 (NF186) and NrCAM, and the scaffolding proteins AnkyrinG (AnkG) and βIV-spectrin (for a more detailed review of the protein components of nodes and their associated domains, see Chang and Rasband, 2013Chang K.J. Rasband M.N. Excitable domains of myelinated nerves: axon initial segments and nodes of Ranvier.Curr. Top. Membr. 2013; 72: 159-192Crossref PubMed Scopus (32) Google Scholar). Nodal clustering of ion channels along the axon confines transmembrane currents to these sites. Together with the reduced membrane capacitance afforded by myelin, nodes greatly increase the speed and efficiency of action potential propagation. Classic studies in several vertebrate species, including humans, show that the internodal length (the distance between nodes of Ranvier [(6) in Figure 2], corresponding to the non-excitable region of the axon) and conduction velocity increase with axon diameter. Therefore, the periodic spacing, or patterning, of nodes helps to determine conduction velocity (Court et al., 2004Court F.A. Sherman D.L. Pratt T. Garry E.M. Ribchester R.R. Cottrell D.F. Fleetwood-Walker S.M. Brophy P.J. Restricted growth of Schwann cells lacking Cajal bands slows conduction in myelinated nerves.Nature. 2004; 431: 191-195Crossref PubMed Scopus (175) Google Scholar). What dictates nodal spacing? In the adult human PNS, internodal lengths for a 10-μm-diameter axon can vary from ∼1 mm in an ulnar nerve to half that in a facial nerve (Vizoso, 1950Vizoso A.D. The relationship between internodal length and growth in human nerves.J. Anat. 1950; 84: 342-353PubMed Google Scholar), indicating that simple fiber diameter does not predict the spacing of nodes along the axon. Instead, nodal spacing increases as an animal grows. For example, nodal spacing in the lower leg of humans can increase 4-fold from birth to young adulthood as height increases (Vizoso, 1950Vizoso A.D. The relationship between internodal length and growth in human nerves.J. Anat. 1950; 84: 342-353PubMed Google Scholar). However, studies in animal models show that there is a limit to the benefits conferred by increasing internodal length and that there is a plateau, above which increasing internodal length has no benefit to conduction velocity (Simpson et al., 2013Simpson A.H. Gillingwater T.H. Anderson H. Cottrell D. Sherman D.L. Ribchester R.R. Brophy P.J. Effect of limb lengthening on internodal length and conduction velocity of peripheral nerve.J. Neurosci. 2013; 33: 4536-4539Crossref PubMed Scopus (41) Google Scholar). Therefore, nodal spacing in the PNS is determined by two properties: the diameter of the axon and the growth of the part of the animal in which the nerve lies. In contrast, the mechanisms controlling nodal spacing in the CNS are more complicated. Although both axon diameter and growth likely influence node spacing, additional activity-dependent mechanisms must also dictate nodal spacing to optimize conduction velocity and tune the properties of CNS circuits. One particularly dramatic example of this is seen in the brainstem auditory circuits that calculate interaural time differences for sound localization. Neurons in the cochlear nucleus have a single bifurcating axon that innervates ipsilateral and contralateral coincidence detector neurons in the brainstem. These two branches of the same axon, with very different lengths, independently adjust their conduction velocities to achieve the precise temporal integration necessary for sound localization. Remarkably, the conduction velocities of these axon branches correlate with axon diameter and node spacing (Seidl et al., 2010Seidl A.H. Rubel E.W. Harris D.M. Mechanisms for adjusting interaural time differences to achieve binaural coincidence detection.J. Neurosci. 2010; 30: 70-80Crossref PubMed Scopus (109) Google Scholar, Seidl et al., 2014Seidl A.H. Rubel E.W. Barría A. Differential conduction velocity regulation in ipsilateral and contralateral collaterals innervating brainstem coincidence detector neurons.J. Neurosci. 2014; 34: 4914-4919Crossref PubMed Scopus (47) Google Scholar). How can two branches from the same axon have different diameters and internodal lengths to control conduction velocity? Although the answer to this question remains unknown, the mechanisms likely depend on local activity-dependent signaling between axons and their closely associated myelinating glial cell, the oligodendrocyte. For example, oligodendrocyte and Schwann cell axon signaling regulates neurofilament phosphorylation and spacing (Perrot et al., 2007Perrot R. Lonchampt P. Peterson A.C. Eyer J. Axonal neurofilaments control multiple fiber properties but do not influence structure or spacing of nodes of Ranvier.J. Neurosci. 2007; 27: 9573-9584Crossref PubMed Scopus (37) Google Scholar), which, in turn, dictates axon diameter (Sánchez et al., 2000Sánchez I. Hassinger L. Sihag R.K. Cleveland D.W. Mohan P. Nixon R.A. Local control of neurofilament accumulation during radial growth of myelinating axons in vivo. Selective role of site-specific phosphorylation.J. Cell Biol. 2000; 151: 1013-1024Crossref PubMed Scopus (132) Google Scholar). Furthermore, because node of Ranvier formation in the CNS requires extrinsic, oligodendrocyte-derived interactions (see below), node locations must also depend on axon-oligodendrocyte signaling. Together, the data suggest that the CNS nodes of Ranvier are not simply static structures that regenerate action potentials but that axons are precisely patterned to optimize conduction velocity and circuit functions. Future studies of axon-oligodendrocyte signaling will be needed to clarify the mechanisms regulating this fascinating form of axonal plasticity. In addition to nodes and internodes, axons are patterned with two other highly organized axonal domains: the paranode (Figure 1F; (4) in Figure 2) and the juxtaparanode (Figure 1F; (5) in Figure 2). Paranodes flank each side of the node and are specialized cell-cell junctions formed between the axonal membrane and the paranodal loops of the myelinating glial cell. Juxtaparanodes are located adjacent to paranodes and beneath the myelin sheath. The paranodal loops correspond to the end of each individual layer of myelin membrane and spiral around the axon to form the largest known vertebrate intercellular junction. The paranodal junction attaches the myelin membrane to the axon, isolates nodal currents from internodes, functions as a barrier to limit the diffusion of membrane proteins in the axolemma, and helps to cluster Na+ channels at nodes (Feinberg et al., 2010Feinberg K. Eshed-Eisenbach Y. Frechter S. Amor V. Salomon D. Sabanay H. Dupree J.L. Grumet M. Brophy P.J. Shrager P. Peles E. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.Neuron. 2010; 65: 490-502Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, Rosenbluth, 2009Rosenbluth J. Multiple functions of the paranodal junction of myelinated nerve fibers.J. Neurosci. Res. 2009; 87: 3250-3258Crossref PubMed Scopus (91) Google Scholar, Susuki et al., 2013Susuki K. Chang K.J. Zollinger D.R. Liu Y. Ogawa Y. Eshed-Eisenbach Y. Dours-Zimmermann M.T. Oses-Prieto J.A. Burlingame A.L. Seidenbecher C.I. et al.Three mechanisms assemble central nervous system nodes of Ranvier.Neuron. 2013; 78: 469-482Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Zonta et al., 2008Zonta B. Tait S. Melrose S. Anderson H. Harroch S. Higginson J. Sherman D.L. Brophy P.J. Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system.J. Cell Biol. 2008; 181: 1169-1177Crossref PubMed Scopus (150) Google Scholar). Juxtaparanodes are characterized by high densities of Kv1 K+ channels (Figure 1F) that are thought to stabilize membrane potential, especially during myelination, after injury, and during remyelination. Juxtaparanodal Kv1 K+ channel clustering requires neuron-glia interactions between axonal Caspr2 (a homolog of the paranodal Caspr) and glial TAG-1 (a homolog of contactin) (Poliak et al., 2003Poliak S. Salomon D. Elhanany H. Sabanay H. Kiernan B. Pevny L. Stewart C.L. Xu X. Chiu S.Y. Shrager P. et al.Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1.J. Cell Biol. 2003; 162: 1149-1160Crossref PubMed Scopus (409) Google Scholar, Savvaki et al., 2010Savvaki M. Theodorakis K. Zoupi L. Stamatakis A. Tivodar S. Kyriacou K. Stylianopoulou F. Karagogeos D. The expression of TAG-1 in glial cells is sufficient for the formation of the juxtaparanodal complex and the phenotypic rescue of tag-1 homozygous mutants in the CNS.J. Neurosci. 2010; 30: 13943-13954Crossref PubMed Scopus (44) Google Scholar). Therefore, clustering of these K+ channels is another example of neuron-glia interactions that pattern the molecular organization of the axonal membrane. Assembly of the paranode depends on interactions between the axonal CAMs Caspr and contactin and the glial 155 kD isoform of neurofascin (NF155) (Bhat et al., 2001Bhat M.A. Rios J.C. Lu Y. Garcia-Fresco G.P. Ching W. St Martin M. Li J. Einheber S. Chesler M. Rosenbluth J. et al.Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin.Neuron. 2001; 30: 369-383Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, Boyle et al., 2001Boyle M.E. Berglund E.O. Murai K.K. Weber L. Peles E. Ranscht B. Li J. Boyle M.E. Berglund E.O. Murai K.K. et al.Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve.Neuron. 2001; 30: 385-397Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, Charles et al., 2002Charles P. Tait S. Faivre-Sarrailh C. Barbin G. Gunn-Moore F. Denisenko-Nehrbass N. Guennoc A.M. Girault J.A. Brophy P.J. Lubetzki C. Neurofascin is a glial receptor for the paranodin/Caspr-contactin axonal complex at the axoglial junction.Curr. Biol. 2002; 12: 217-220Abstract Full Text Full Text PDF PubMed Scopus (242) Google Scholar, Pillai et al., 2009Pillai A.M. Thaxton C. Pribisko A.L. Cheng J.G. Dupree J.L. Bhat M.A. Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains.J. Neurosci. Res. 2009; 87: 1773-1793Crossref PubMed Scopus (147) Google Scholar). Interestingly, like nodes, paranodes are also enriched with ankyrins and spectrins. In the peripheral nervous system, AnkyrinB, βII spectrin, and αII spectrin can be found at paranodes (Ogawa et al., 2006Ogawa Y. Schafer D.P. Horresh I. Bar V. Hales K. Yang Y. Susuki K. Peles E. Stankewich M.C. Rasband M.N. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton.J. Neurosci. 2006; 26: 5230-5239Crossref PubMed Scopus (136) Google Scholar). In the CNS, AnkG is found at paranodes (Rasband et al., 1999Rasband M.N. Peles E. Trimmer J.S. Levinson S.R. Lux S.E. Shrager P. Dependence of nodal sodium channel clustering on paranodal axoglial contact in the developing CNS.J. Neurosci. 1999; 19: 7516-7528Crossref PubMed Google Scholar). We showed recently that paranodal ankyrins are found in the myelinating glia, where they interact with NF155. Genetic ablation of AnkG from oligodendrocytes causes a profound delay in the formation and maturation of paranodal junctions (Chang et al., 2014Chang K.J. Zollinger D.R. Susuki K. Sherman D.L. Makara M.A. Brophy P.J. Cooper E.C. Bennett V. Mohler P.J. Rasband M.N. Glial ankyrins facilitate paranodal axoglial junction assembly.Nat. Neurosci. 2014; 17: 1673-1681Crossref PubMed Scopus (67) Google Scholar). In axons, assembly of the spectrin-based paranodal cytoskeleton is thought to depend on the adaptor protein 4.1B, which links Caspr to spectrins. Axons lacking protein 4.1B or βII-spectrin have disrupted ion channel clustering and similar phenotypes; proteins normally restricted to juxtaparanodes invade neighboring paranodal domains (Horresh et al., 2010Horresh I. Bar V. Kissil J.L. Peles E. Organization of myelinated axons by Caspr and Caspr2 requires the cytoskeletal adapter protein 4.1B.J. Neurosci. 2010; 30: 2480-2489Crossref PubMed Scopus (86) Google Scholar, Zhang et al., 2013Zhang C. Susuki K. Zollinger D.R. Dupree J.L. Rasband M.N. Membrane domain organization of myelinated axons requires βII spectrin.J. Cell Biol. 2013; 203: 437-443Crossref PubMed Scopus (57) Google Scholar). Therefore, spectrin-based paranodal submembranous cytoskeletons may be viewed as cytoskeletal boundaries that organize the axon into repeating units of excitable and non-excitable membrane domains. The assembly of these paranodal boundaries depends on axon-glia interactions. Loss of Caspr, contactin, or NF155 impairs paranodal junction formation and assembly of the paranodal cytoskeleton, and proteins normally restricted to juxtaparanodes enter paranodal domains (Bhat et al., 2001Bhat M.A. Rios J.C. Lu Y. Garcia-Fresco G.P. Ching W. St Martin M. Li J. Einheber S. Chesler M. Rosenbluth J. et al.Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/Paranodin.Neuron. 2001; 30: 369-383Abstract Full Text Full Text PDF PubMed Scopus (467) Google Scholar, Boyle et al., 2001Boyle M.E. Berglund E.O. Murai K.K. Weber L. Peles E. Ranscht B. Li J. Boyle M.E. Berglund E.O. Murai K.K. et al.Contactin orchestrates assembly of the septate-like junctions at the paranode in myelinated peripheral nerve.Neuron. 2001; 30: 385-397Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar, Ogawa et al., 2006Ogawa Y. Schafer D.P. Horresh I. Bar V. Hales K. Yang Y. Susuki K. Peles E. Stankewich M.C. Rasband M.N. Spectrins and ankyrinB constitute a specialized paranodal cytoskeleton.J. Neurosci. 2006; 26: 5230-5239Crossref PubMed Scopus (136) Google Scholar, Pillai et al., 2009Pillai A.M. Thaxton C. Pribisko A.L. Cheng J.G. Dupree J.L. Bhat M.A. Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains.J. Neurosci. Res. 2009; 87: 1773-1793Crossref PubMed Scopus (147) Google Scholar). Although the paranodes, juxtaparanodes, and internodes are excellent examples of axonal patterning, the clustering of Na+ channels at the nodes of Ranvier remains the prototypical and, arguably, the most interesting and complex example of subcellular axonal patterning. What molecular and cellular mechanisms are responsible for nodal Na+ channel clustering? Remarkably, for this important process, two glial mechanisms have been identified that work together to assemble nodes of Ranvier. These mechanisms include a glia-derived extracellular matrix and cell adhesion molecule protein complex that interacts with and clusters axonal transmembrane NF186 and a paranodal junction-dependent membrane barrier that limits the lateral diffusion of axonal membrane proteins like NF186. These mechanisms converge on AnkG and βIV spectrin because they bind, stabilize, and link Na+ channels and NF186 to the underlying cytoskeleton (Feinberg et al., 2010Feinberg K. Eshed-Eisenbach Y. Frechter S. Amor V. Salomon D. Sabanay H. Dupree J.L. Grumet M. Brophy P.J. Shrager P. Peles E. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.Neuron. 2010; 65: 490-502Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, Susuki et al., 2013Susuki K. Chang K.J. Zollinger D.R. Liu Y. Ogawa Y. Eshed-Eisenbach Y. Dours-Zimmermann M.T. Oses-Prieto J.A. Burlingame A.L. Seidenbecher C.I. et al.Three mechanisms assemble central nervous system nodes of Ranvier.Neuron. 2013; 78: 469-482Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar, Zonta et al., 2008Zonta B. Tait S. Melrose S. Anderson H. Harroch S. Higginson J. Sherman D.L. Brophy P.J. Glial and neuronal isoforms of Neurofascin have distinct roles in the assembly of nodes of Ranvier in the central nervous system.J. Cell Biol. 2008; 181: 1169-1177Crossref PubMed Scopus (150) Google Scholar). Ankyrin/spectrin protein complexes function as key structural and scaffolding proteins to pattern the axon. Traditionally, one α- and one β-spectrin subunit combine to form a heterodimer. Two of these heterodimers interact in an anti-parallel arrangement to form a functional tetramer. Spectrin tetramers bind simultaneously to filamentous actin at each end and to ankyrins at the central region of the tetramer through the β-spectrin subunits. The actin/spectrin/ankyrin complex has been studied extensively in erythrocytes, where it anchors membrane proteins and provides structural stability and elasticity to the cell's membrane (Bennett and Lorenzo, 2013Bennett V. Lorenzo D.N. Spectrin- and ankyrin-based membrane domains and the evolution of vertebrates.Curr. Top. Membr. 2013; 72: 1-37Crossref PubMed Scopus (99) Google Scholar). Interestingly, although PNS and CNS nodes both have clustered axonal Na+ channels, NF186, AnkG, and βIV spectrin, their glia-driven mechanisms of assembly follow different sequences of events and even use different molecules. The first event leading to Na+ channel clustering in axons is the glia-dependent clustering of NF186 within the axonal membrane (Lambert et al., 1997Lambert S. Davis J.Q. Bennett V. Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates.J. Neurosci. 1997; 17: 7025-7036Crossref PubMed Google Scholar, Schafer et al., 2006Schafer D.P. Custer A.W. Shrager P. Rasband M.N. Early events in node of Ranvier formation during myelination and remyelination in the PNS.Neuron Glia Biol. 2006; 2: 69-79Crossref PubMed Scopus (66) Google Scholar, Susuki et al., 2013Susuki K. Chang K.J. Zollinger D.R. Liu Y. Ogawa Y. Eshed-Eisenbach Y. Dours-Zimmermann M.T. Oses-Prieto J.A. Burlingame A.L. Seidenbecher C.I. et al.Three mechanisms assemble central nervous system nodes of Ranvier.Neuron. 2013; 78: 469-482Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). In the PNS, NF186 is initially clustered through interactions with gliomedin and NrCAM, which are found on microvilli at each end of the elongating Schwann cell ((3) in Figure 3A, peripheral nervous system). Gliomedin and NrCAM interact with other extracellular matrix (ECM) molecules to assemble a multimolecular protein complex that functions as a high-avidity clustering complex for NF186 (Eshed et al., 2007Eshed Y. Feinberg K. Carey D.J. Peles E. Secreted gliomedin is a perinodal matrix component of peripheral nerves.J. Cell Biol. 2007; 177: 551-562Crossref PubMed Scopus (87) Google Scholar, Feinberg et al., 2010Feinberg K. Eshed-Eisenbach Y. Frechter S. Amor V. Salomon D. Sabanay H. Dupree J.L. Grumet M. Brophy P.J. Shrager P. Peles E. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.Neuron. 2010; 65: 490-502Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). In contrast, gliomedin is not found at nodes in the CNS. Instead, paranodal junctions form before the clustering of NF186. As myelin elongates and the paranodal junction migrates along the axon, it accumulates NF186 adjacent to the paranodal junction ((1) in Figure 3A, CNS). In both the PNS and CNS, clustered NF186 then acts as an attachment site to recruit its direct binding partner, AnkG ((3) in Figure 3A). Although the primary mechanism of Na+ channel clustering in the PNS is through gliomedin/NrCAM-dependent clustering of NF186, a secondary, paranodal junction-dependent mechanism can also support Na+ channel clustering ((2) in Figure 3A, PNS). For example, gliomedin- and NrCAM-null mice still cluster NF186, AnkG, and Na+ channels, but mice lacking both gliomedin and paranodal junctions do not form Na+ channel clusters (Feinberg et al., 2010Feinberg K. Eshed-Eisenbach Y. Frechter S. Amor V. Salomon D. Sabanay H. Dupree J.L. Grumet M. Brophy P.J. Shrager P. Peles E. A glial signal consisting of gliomedin and NrCAM clusters axonal Na+ channels during the formation of nodes of Ranvier.Neuron. 2010; 65: 490-502Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar). Similarly, although paranodal junction barriers function as the primary mechanism of Na+ channel clustering in the CNS, loss of paranodal junctions does not block Na+ channel clustering. Instead, a second mechanism that depends on interactions between NF186 and a complex set of glia-derived ECM proteins (analogous to the gliomedin/NrCAM-NF186 interactions in the PNS) can substitute for paranodal junctions to assemble CNS nodes ((2) in Figure 3A, CNS). In support of this idea, mice lacking both paranodal junctions and CNS nodal ECM proteins die in the first 3 weeks of age and have severely impaired CNS nodal Na+ channel clustering (Susuki et al., 2013Susuki K. Chang K.J. Zollinger D.R. Liu Y. Ogawa Y. Eshed-Eisenbach Y. Dours-Zimmermann M.T. Oses-Prieto J.A. Burlingame A.L. Seidenbecher C.I. et al.Three mechanisms assemble central nervous system nodes of Ranvier.Neuron. 2013; 78: 469-482Abstract Full Text Full Text PDF PubMed Scopus (119) Google Scholar). As described above, the two glia-dependent node assembly mechanisms converge on AnkG to initiate clustering of Na+ channels ((4) in Figure 3A). Na+ channels have an intracellular ankyrin-binding motif (Garrido et al., 2003Garrido J.J. Giraud P. Carlier E. Fernandes F. Moussif A. Fache M.P. Debanne D. Dargent B. A targeting motif involved in sodium channel clustering at the axonal initial segment.Science. 2003; 300: 2091-2094Crossref PubMed Scopus (280) Google Scholar, Lemaillet et al., 2003Lemaillet G. Walker B. Lambert S. Identification of a conserved ankyrin-binding motif in the family of sodium channel alpha subunits.J. Biol. Chem. 2003; 278: 27333-27339Crossref PubMed Scopus (206) Google Scholar) that is both necessary and sufficient for Na+ channel clustering at nodes (Gasser et al., 2012Gasser A. Ho T.S.-Y. Cheng X. Chang K.J. Waxman S.G. Rasband M.N. Dib-Hajj S.D. An ankyrinG-binding motif is necessary and sufficient for targeting Nav1.6 sodium channels to axon initial segments and nodes of Ranvier.J. Neurosci. 2012; 32: 7232-7243Crossref PubMed Scopus (93) Google Scholar). The nodal AnkG/Na+ channel complex is stabilized through its association with the βIV spectrin-based submembranous cytoskeleton. Remarkably, during early development or in the absence of AnkG or βIV spectrin, a second ankyrin/spectrin cytoskeletal complex consisting of AnkyrinR and βI spectrin can cluster nodal Na+ channels (Ho et al., 2014Ho T.S. Zollinger D.R. Chang K.J. Xu M. Cooper E.C. Stankewich M.C. Bennett V. Rasband M.N. A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier.Nat. Neurosci. 2014; 17: 1664-1672Crossref PubMed Scopus (72) Google Scholar). AnkR/βI spectrin complexes, normally thought to functional mainly in erythrocytes, are present in adult myelinated axons but not clustered at nodes. AnkR/βI spectrin has a lower affinity for NF186 and Na+ channels compared with AnkG/βIV spectrin. This difference in affinities results in a hierarchy of clustering activities with AnkG/βIV spectrin as primary and AnkR/βI spectrin as secondary clustering mechanisms. Loss of both AnkR and AnkG completely blocks the clustering of nodal Na+ channels (Ho et al., 2014Ho T.S. Zollinger D.R. Chang K.J. Xu M. Cooper E.C. Stankewich M.C. Bennett V. Rasband M.N. A hierarchy of ankyrin-spectrin complexes clusters sodium channels at nodes of Ranvier.Nat. Neurosci. 2014; 17: 1664-1672Crossref PubMed Scopus (72) Google Scholar). The importance of the glia-driven clustering mechanisms and the axonal cytoskeleton for CNS node formation has been shown further in mice that lacked nodal βIV spectrin and either the parano
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