Spatiotemporal ablation of myelinating glia-specific neurofascin (Nfasc NF155) in mice reveals gradual loss of paranodal axoglial junctions and concomitant disorganization of axonal domains.
ABSTRACT The evolutionary demand for rapid nerve impulse conduction led to the process of myelination-dependent organization of axons into distinct molecular domains. These domains include the node of Ranvier flanked by highly specialized paranodal domains where myelin loops and axolemma orchestrate the axoglial septate junctions. These junctions are formed by interactions between a glial isoform of neurofascin (Nfasc(NF155)) and axonal Caspr and Cont. Here we report the generation of myelinating glia-specific Nfasc(NF155) null mouse mutants. These mice exhibit severe ataxia, motor paresis, and death before the third postnatal week. In the absence of glial Nfasc(NF155), paranodal axoglial junctions fail to form, axonal domains fail to segregate, and myelinated axons undergo degeneration. Electrophysiological measurements of peripheral nerves from Nfasc(NF155) mutants revealed dramatic reductions in nerve conduction velocities. By using inducible PLP-CreER recombinase to ablate Nfasc(NF155) in adult myelinating glia, we demonstrate that paranodal axoglial junctions disorganize gradually as the levels of Nfasc(NF155) protein at the paranodes begin to drop. This coincides with the loss of the paranodal region and concomitant disorganization of the axonal domains. Our results provide the first direct evidence that the maintenance of axonal domains requires the fence function of the paranodal axoglial junctions. Together, our studies establish a central role for paranodal axoglial junctions in both the organization and the maintenance of axonal domains in myelinated axons.
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ABSTRACT: The presence of intact paranodal junctions on myelinated axons in the CNS and PNS is crucial for both myelin sheath attachment and saltatory impulse conduction. The axonal glycoprotein contactin-associated protein (Caspr) is expressed in the paranodal region and plays an important role in the creation and maintenance of these adhesive junctions. In the present study, antibodies to Caspr were used to assess the integrity of paranodal junctions on myelinated axons in brain and spinal cord tissue from subjects with longstanding multiple sclerosis, a neurological disorder that affects both myelin and axons. Triple immunofluorescence combined with confocal laser scanning microscopy showed that axons in the demyelinated centre of the 36 brain and 16 spinal cord multiple sclerosis lesions studied were devoid of Caspr immunoreactivity, suggesting that axons down regulate the expression of Caspr following demyelination. Additional data indicated that Caspr reappears in the paranodal region with the formation of new myelin sheaths. Immuno labelling further revealed that Caspr on myelinated axons in border regions was often no longer concentrated in the paranodal region, but was also present in the internodal region-a phenomenon particularly common in the borders of the more chronic lesions in the collection. Myelinated axons with long Caspr-positive stretches were often present at a considerable distance from the lesion edges. These findings raise the possibility that the aberrant location of Caspr is an early sign of impending myelin loss. This would imply that demyelination continues at a slow rate in established lesions. The diameters of Caspr-positive structures on some myelinated axons near the lesion edges were also increased. Moreover, the gap between individual myelin sheaths on these apparently swollen axons was widened occasionally and a very small myelin sheath plus additional Caspr-positive structures had sometimes formed in the enlarged space. This finding thus suggests that the formation of new myelin in multiple sclerosis is not only induced following the loss of complete internodes but also in response to broadening of the nodal region. Interestingly, alterations in the expression and localization of Caspr were observed in tissue from both subjects with the primary and secondary progressive form of multiple sclerosis. In summary, the present study provides immunohistochemical evidence that paranodal junctions on some myelinated axons in the borders of lesions of patients with chronic progressive multiple sclerosis are no longer intact. This may impair saltatory impulse conduction and lead to further myelin loss, thereby contributing to disease progression in multiple sclerosis.Brain 08/2003; 126(Pt 7):1638-49. · 9.92 Impact Factor
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ABSTRACT: Action potential conduction velocity increases dramatically during early development as axons become myelinated. Integral to this process is the clustering of voltage-gated Na(+) (Nav) channels at regularly spaced gaps in the myelin sheath called nodes of Ranvier. We show here that some aspects of peripheral node of Ranvier formation are distinct from node formation in the CNS. For example, at CNS nodes, Nav1.2 channels are detected first, but are then replaced by Nav1.6. Similarly, during remyelination in the CNS, Nav1.2 channels are detected at newly forming nodes. By contrast, the earliest Nav-channel clusters detected during developmental myelination in the PNS have Nav1.6. Further, during PNS remyelination, Nav1.6 is detected at new nodes. Finally, we show that accumulation of the cell adhesion molecule neurofascin always precedes Nav channel clustering in the PNS. In most cases axonal neurofascin (NF-186) accumulates first, but occasionally paranodal neurofascin is detected first. We suggest there is heterogeneity in the events leading to Nav channel clustering, indicating that multiple mechanisms might contribute to node of Ranvier formation in the PNS.Neuron Glia Biology 06/2006; 2(2):69-79. · 1.34 Impact Factor
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ABSTRACT: Myelination organizes axons into distinct domains that allow nerve impulses to propagate in a saltatory manner. The edges of the myelin sheath are sealed at the paranodes by axon-glial junctions that have a crucial role in organizing the axonal cytoskeleton. Here we propose a model in which the myelinated axons depend on the axon-glial junctions to stabilize the cytoskeletal transition at the paranodes. Thus paranodal regions are likely to be particularly susceptible to damage induced by demyelinating diseases such as multiple sclerosis.Neuron Glia Biology 06/2007; 3(2):169-78. · 1.34 Impact Factor