The ensheathment and myelination of axons during development proceeds in a series of steps that requires complex and reciprocal interactions between axons and the myelinating cells (Figure 8.8). In the first phase, oligodendrocytes and Schwann cells have to recognize axons that require myelination. In a second phase, the processes of the premyelinating cell must adhere to the axons and begin to ensheath them. In a third phase, axons and the myelinating cells pass through a series of interdependent maturation stages. How do the myelinating cells recognize axons to be myelinated? What determines the longitudinal and radial growth of the myelin sheath? How do the myelinating cells regulate the radial growth of axons and what are the signals that determine the differential and highly specialized organization of the axolemma and myelin sheaths at nodes of Ranvier, paranodes, and juxtaparanodes? We do not know the answers to these questions, but there is clear evidence of crucial roles for a number of candidate molecular cues and signals. The answers to these questions will also be relevant to the regulation of remyelination in demyelinating diseases and following regeneration.
Phase 1 - Axon contact: Axon diameter is a critical determinant of myelination in the PNS, and axons are not myelinated until they attain a critical diameter of approximately 0.7 ^m. Axon diameter plays a less definitive role in the CNS, but nonetheless CNS axons are not myelinated below 0.2 ^m and the initiation of myelination only occurs when axons have reached this 'critical' diameter. How the myelinating cells recognize axons of a critical diameter is not yet resolved, but the axonal surface proteins NCAM and L1 are key candidates for negative and positive recognition signals. Disappearance of NCAM from the axonal surface is coincident with the onset of myelination, and suppression of NCAM stimulates myelination. Thus, myelinating cells may distinguish axons that are, and are not, ready for myelination by their differential expression of NCAM. L1 is another adhesion molecule expressed at the axon surface and has a demonstrated function in axon recognition in the PNS and most likely functions in the same way in the CNS. L1 is expressed by premyelinated axons and is down-regulated during myelination. Disruption of L1 strongly inhibits myelination, suggesting an inductive role for L1 in the initiation of myelination (although the L1 knockout mouse shows no abnormalities in myelination). The binding partners for NCAM and L1 in oligodendrocytes have not been identified. In Schwann cells, integrins and periaxin are important in axo-glial interactions. Oligodendrocytes do not express periaxin,
Figure 8.8 Myelination. During development, myelination proceeds in a series of steps that require complex and reciprocal interactions between axons and the myelinating cells (an oligodendrocyte is illustrated). In essence, these interactions are the same in the PNS and CNS, although specific signals regulating myelination may differ; a major difference is that Schwann cells identify a single axon which they myelinate, whereas oligodendrocytes identify multiple axons that require myelination and the definitive number depends on oligodendrocyte phenotype and axon diameter. Phase 1 - the premyelinating Schwann cell or oligodendrocyte contacts many premyelinated axons, but only those that have attained a critical diameter are myelinated; the recognition and adhesion signals are unresolved, but are likely to involve interactions between membrane surface molecules on the myelinating cell and axon. Phase 2 - the myelinating cell ensheaths the axon, which requires process adhesion and longitudinal growth; the adhesion molecules have not been identified, although cell surface molecules are again likely candidates, and include MAG and NCAM. At this stage, oligodendrocytes undergo remodelling, when nonensheathing processes are lost and the definitive number of sheaths per unit is established; this is strictly dependent on the diameter of axons in the unit, but the signals controlling oligo-dendrocyte phenotype (I-IV) divergence are unresolved. Phases 3 and 4 - axons and the myelin sheath undergo interdependent growth and maturation. Myelin sheaths become compacted and the number of lamellae increases as the axons grow in diameter. Nodes of Ranvier are established (see Figure 8.11) and internodal myelin sheaths grow in direct relationship to the thickening of axons. The longitudinal and radial growth of the myelin sheath and axons, and the organization of the axolemma and myelin sheaths at nodes of Ranvier, paranodes, and juxtaparanodes must involve highly complex molecular cues and signals (see the text for more details)
but specific integrins expressed on oligodendrocytes promote either differentiation and/or proliferation, dependent on the Src family kinases (SFKs) Fyn and Lyn. Early in the lineage, Lyn drives integrin-dependent progenitor proliferation, whereas at later stages Fyn regulates integrin-driven myelin formation and switches the response to neuregulin signalling from proliferation to differentiation. There is experimental evidence that N-cadherin may be important for the initial contact between myelinating oligodendrocytes and axons. Oligodendrocytes also express neurofascin, which is a ligand for the axonal L1 CAM family, but these interactions are likely to play a later role in myelination rather than axon contact and recognition.
Contact with axons stimulates the differentiation of OPCs into premyelinating oligodendrocytes, which begin to sequentially express myelin-related gene products GalC, CNP, PLP/DM20, S-MAG and MBP, prior to axonal ensheathment. Neuregulin-1 and Jagged/Notch signalling are key negative and positive regulators of oligodendrocyte differentiation, respectively. (However, in vitro oligodendrocytes will differentiate and form myelin in appropriate culture conditions in the absence of axons.) Down-regulation of axonal Jagged is required for OPC differentiation, and Jagged/Notch signalling may play a particular role in the onset of myelination. Axonal neuregulin-1 induces differentiation of oligodendrocytes in vitro. Disruption of neuregulin-1 signalling in vitro and the absence of the neuregulin receptor ErbB2 in vivo blocks OPC differentiation and myelin formation. In addition, interactions between axonal contactin and Notch receptors on OPCs play an instructive role by promoting OPC differentiation and up-regulation of myelin proteins. In the PNS, NRG-1 type III on axons determines their ensheathment fate, independent of axon diameter, and provides a key instructive signal for Schwann cell myelination.
Phase 2 - Axon ensheathment and establishment of incipient internodal myelin segments: Premyelinating oligodendrocytes that engage axons ready for myelination extend an 'initiator' process that begins to spiral along the axon. The adhesion molecules have not been identified, although MAG and PLP are attractive candidates because of their functions in cell-cell interactions and their timely expression by premyelinating oligodendrocytes. Studies in culture and knockout mice indicate a key role for MAG and NCAM in the initiation of myelination; MAG may increase Fyn tyrosine kinase activity, which is an essential signalling component for oligodendrocyte process outgrowth. Studies in jimpy mice indicate that PLP is essential for oligodendrocytes to properly associate with and then ensheath axons. Other signalling molecules such as Tspan-2, neurofascin, and CD9 are abundant in myelinating oligodendrocytes and their processes, and are important for axo-glial interactions, but are probably not essential for the initiation of myelination. Premyelinating oligodendrocytes engage and ensheath multiple axons within 10-30 ^m of their cell body. They then go through a remodelling phase, when nonensheathing processes are lost and the definitive number of sheaths per unit is established. The initial lamellar ensheathments are uncompacted (termed
E-sheaths). The clustering of sodium channels at nodes of Ranvier is initiated by these contacts, but functional nodes are established later when incipient internodes have grown (see Chapter 8.4.1). The E-sheaths and presumptive nodes are sufficient to support conduction of axonal action potentials, and they develop concurrently. After the first encirclement of axons, the myelin sheath begins to become compacted (termed M-sheaths) and individual oligodendrocyte units can contain both E- and M-sheaths. The number of axons per oligodendrocyte unit decreases throughout the transition from uncompacted to compacted myelin sheaths. This remodelling occurs in response to unresolved contact-mediated recognition signals derived from axons within the unit, which could be qualitatively and/or quantitatively different for prospective large and small diameter axons. Incipient internodal lengths are also established during the transition to compact myelin, and they have relatively uniform lengths within individual units, subsequently growing symmetrically along the axons to attain their definitive lengths. The longitudinal and radial growth of the myelin sheath is directly dependent on the diameter of axons in the unit. It is not known how myelinated internodal segments become serially arranged along an axon and ultimately attain approximately equal lengths to give rise to the nodal periodicity, which is uniform for any axon of a given diameter. Galactolipids are essential for the internodal myelin spacing, but it seems unlikely they provide the instructive cues.
Phase 3/4 - Remodelling and maturation: After the initial circumnavigation of an axon by a noncompacted sheath, subsequent wraps of the sheath must interact with and fuse to each other, which is dependent on PLP and MBP. The absence of PLP also results in axonal degeneration, indicating a continuing role for PLP in axon-myelin interactions. Longitudinal growth of the myelin sheath is accompanied by maturation of paranodal axo-glial junctions and the maturation of nodes of Ranvier. Knockout studies indicate the development of paranodal axo-glial junctions requires galactolipids, sulphatides, MAG, CNP and connexins. Neurofascin plays a particular role in the establishment of nodes of Ranvier. Maturation of the axon and myelin sheath are interdependent. Radial growth of axons and sodium channel clustering at nodes are dependent on oligodendrocyte and Schwann cell contact. Studies in knockout mice demonstrate that axonal integrity depends on PLP, CNP and GalC. Conversely, loss of axons results in the down-regulation of myelin-related gene products in oligodendrocytes and eventually cell death.
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