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Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1.

Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu SY, Shrager P, Furley AJ, Peles E - J. Cell Biol. (2003)

Bottom Line: In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily.Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location.These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.

ABSTRACT
In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K+ channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

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Morphology of the nodal environs in Caspr2−/− mice. EM pictures of cross (A and E) and longitudinal (B and F) sections of sciatic nerve from adult wild-type (+/+; A and B), or Caspr2-deficient (−/−; E and F) mice are shown. Red arrowheads mark the location of the juxtaparanodes. C, D, G, and H (+/+, C and D; −/−, G and H), show double-immunofluorescence staining of the nodal region using antibodies to Na+ channels (red) and Caspr (green; C and G) or to NF155 (green; D and H). Bars: A and E, 200 nm; B and F, 1 μm.
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fig2: Morphology of the nodal environs in Caspr2−/− mice. EM pictures of cross (A and E) and longitudinal (B and F) sections of sciatic nerve from adult wild-type (+/+; A and B), or Caspr2-deficient (−/−; E and F) mice are shown. Red arrowheads mark the location of the juxtaparanodes. C, D, G, and H (+/+, C and D; −/−, G and H), show double-immunofluorescence staining of the nodal region using antibodies to Na+ channels (red) and Caspr (green; C and G) or to NF155 (green; D and H). Bars: A and E, 200 nm; B and F, 1 μm.

Mentions: Homozygous Caspr2 mutants were born with the expected Mendelian frequency and their appearance was normal. Although generally, Caspr2−/− pups were smaller than their heterozygous littermates, this size difference was completely overcome by the second to third month of age (unpublished data). Histological examination revealed no gross abnormalities in the brain of homozygous mice (unpublished data). In contrast to Caspr-deficient mice, which display ataxia and tremor and motor deficits (Bhat et al., 2001; unpublished data), Caspr2 s exhibited no signs of neurological abnormalities in their first 20 months of age. Ultrastructural analysis using transmission EM of sciatic nerves (Fig. 2), as well as optic nerves and spinal cords (unpublished data), showed normal myelin formation and a typical morphology of the nodal environs. The nodes of Ranvier, paranodal septa at the axoglial junction, and the juxtaparanodal region in Caspr2−/− were indistinguishable from wild-type animals. In agreement, immunofluorescence labeling using Na+ channels and Caspr or NF155 demonstrated that these proteins were normally localized at the nodes of Ranvier and paranodal junctions, respectively (Fig. 2, G and H). Furthermore, morphometric analysis of optic and sciatic nerves from wild-type and homozygous Caspr2−/− mice showed comparable values of axonal caliber, myelin thickness, and G ratios (G ratios: optic nerve, WT 0.79 ± 0.05, KO 0.80 ± 0.05; sciatic nerve: WT, 0.65 ± 0.05, KO 0.65 ± 0.04, n = 150/genotype). These analyses indicate that the absence of Caspr2 did not affect myelin formation, axonal ensheathment, or the nodal architecture.


Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1.

Poliak S, Salomon D, Elhanany H, Sabanay H, Kiernan B, Pevny L, Stewart CL, Xu X, Chiu SY, Shrager P, Furley AJ, Peles E - J. Cell Biol. (2003)

Morphology of the nodal environs in Caspr2−/− mice. EM pictures of cross (A and E) and longitudinal (B and F) sections of sciatic nerve from adult wild-type (+/+; A and B), or Caspr2-deficient (−/−; E and F) mice are shown. Red arrowheads mark the location of the juxtaparanodes. C, D, G, and H (+/+, C and D; −/−, G and H), show double-immunofluorescence staining of the nodal region using antibodies to Na+ channels (red) and Caspr (green; C and G) or to NF155 (green; D and H). Bars: A and E, 200 nm; B and F, 1 μm.
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fig2: Morphology of the nodal environs in Caspr2−/− mice. EM pictures of cross (A and E) and longitudinal (B and F) sections of sciatic nerve from adult wild-type (+/+; A and B), or Caspr2-deficient (−/−; E and F) mice are shown. Red arrowheads mark the location of the juxtaparanodes. C, D, G, and H (+/+, C and D; −/−, G and H), show double-immunofluorescence staining of the nodal region using antibodies to Na+ channels (red) and Caspr (green; C and G) or to NF155 (green; D and H). Bars: A and E, 200 nm; B and F, 1 μm.
Mentions: Homozygous Caspr2 mutants were born with the expected Mendelian frequency and their appearance was normal. Although generally, Caspr2−/− pups were smaller than their heterozygous littermates, this size difference was completely overcome by the second to third month of age (unpublished data). Histological examination revealed no gross abnormalities in the brain of homozygous mice (unpublished data). In contrast to Caspr-deficient mice, which display ataxia and tremor and motor deficits (Bhat et al., 2001; unpublished data), Caspr2 s exhibited no signs of neurological abnormalities in their first 20 months of age. Ultrastructural analysis using transmission EM of sciatic nerves (Fig. 2), as well as optic nerves and spinal cords (unpublished data), showed normal myelin formation and a typical morphology of the nodal environs. The nodes of Ranvier, paranodal septa at the axoglial junction, and the juxtaparanodal region in Caspr2−/− were indistinguishable from wild-type animals. In agreement, immunofluorescence labeling using Na+ channels and Caspr or NF155 demonstrated that these proteins were normally localized at the nodes of Ranvier and paranodal junctions, respectively (Fig. 2, G and H). Furthermore, morphometric analysis of optic and sciatic nerves from wild-type and homozygous Caspr2−/− mice showed comparable values of axonal caliber, myelin thickness, and G ratios (G ratios: optic nerve, WT 0.79 ± 0.05, KO 0.80 ± 0.05; sciatic nerve: WT, 0.65 ± 0.05, KO 0.65 ± 0.04, n = 150/genotype). These analyses indicate that the absence of Caspr2 did not affect myelin formation, axonal ensheathment, or the nodal architecture.

Bottom Line: In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily.Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location.These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.

ABSTRACT
In myelinated axons, K+ channels are concealed under the myelin sheath in the juxtaparanodal region, where they are associated with Caspr2, a member of the neurexin superfamily. Deletion of Caspr2 in mice by gene targeting revealed that it is required to maintain K+ channels at this location. Furthermore, we show that the localization of Caspr2 and clustering of K+ channels at the juxtaparanodal region depends on the presence of TAG-1, an immunoglobulin-like cell adhesion molecule that binds Caspr2. These results demonstrate that Caspr2 and TAG-1 form a scaffold that is necessary to maintain K+ channels at the juxtaparanodal region, suggesting that axon-glia interactions mediated by these proteins allow myelinating glial cells to organize ion channels in the underlying axonal membrane.

Show MeSH
Related in: MedlinePlus