title: Genetic dysmyelination alters the molecular architecture of the nodal region.
abstract: We have examined the molecular organization of axons in the spinal cords of myelin-deficient (md) rats, which have profound CNS dysmyelination associated with oligodendrocyte cell death. Although myelin sheaths are rare, most large axons are at least partially surrounded by oligodendrocyte processes. At postnatal day 7 (P7), almost all node-like clusters of voltage-gated Na+ channels and ankyrinG are adjacent to axonal segments ensheathed by oligodendrocytes, but at P21, many node-like clusters are found in axonal segments that lack oligodendrocyte ensheathment. In P21 wild-type (WT) rats, the voltage-gated Na+ channels Na(v)1.2, Na(v)1.6, and Na(v)1.8, are found in different subpopulations of myelinated axons, and md rats have a similar distribution. The known molecular components of paranodes--contactin, Caspr, and neurofascin 155--are not clustered in md spinal cords, and no septate-like junctions between oligodendrocyte processes and axons are found by electron microscopy. Furthermore, Kv1.1 and Kv1.2 K+ channels are not spatially segregated from the node-like clusters of Na+ channels in md rats, in contrast to their WT littermates. These results suggest the following: node-like clusters of voltage-gated Na+ channels and ankyrinG form adjacent to ensheathed axonal segments even in the absence of a myelin sheath; these clusters persist after oligodendrocyte cell death; dysmyelination does not alter the expression of different nodal of voltage-gated Na+ channels; the absence of paranodes results in the mislocalization of neurofascin155, contactin, and Caspr, and the aberrant localization of Kv1.1 and Kv1.2.
authors.affiliation: Department of Neurology, The University of Pennsylvania Medical Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104-6077, USA.
authors.forename: Edgardo J
authors.initials: EJ
authors.lastname: Arroyo
authors.forename: Theodore
authors.initials: T
authors.lastname: Xu
authors.forename: Judith
authors.initials: J
authors.lastname: Grinspan
authors.forename: Stephen
authors.initials: S
authors.lastname: Lambert
authors.forename: S Rock
authors.initials: SR
authors.lastname: Levinson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Brophy
authors.forename: Elior
authors.initials: E
authors.lastname: Peles
authors.forename: Steven S
authors.initials: SS
authors.lastname: Scherer
mesh_terms: D000818:Animals; D017487:Ankyrins / Q000096:biosynthesis; D001369:Axons / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D003711:Demyelinating Diseases / Q000235:genetics* / Q000473:pathology*; D051662:Kv1.1 Potassium Channel; D051663:Kv1.2 Potassium Channel; D008297:Male; D009186:Myelin Sheath / Q000473:pathology*; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D015221:Potassium Channels / Q000096:biosynthesis; D024642:Potassium Channels, Voltage-Gated; D011901:Ranvier's Nodes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D051381:Rats; D011922:Rats, Mutant Strains; D015222:Sodium Channels / Q000096:biosynthesis; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure
chemical_list: D017487:Ankyrins; C496972:Kcna2 protein, rat; D051663:Kv1.2 Potassium Channel; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D015222:Sodium Channels; D051662:Kv1.1 Potassium Channel