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Tight junctions in Schwann cells of peripheral myelinated axons: a lesson from claudin-19-deficient mice.

Miyamoto T, Morita K, Takemoto D, Takeuchi K, Kitano Y, Miyakawa T, Nakayama K, Okamura Y, Sasaki H, Miyachi Y, Furuse M, Tsukita S - J. Cell Biol. (2005)

Bottom Line: Claudin-19-deficient mice were generated, and they exhibited behavioral abnormalities that could be attributed to peripheral nervous system deficits.Interestingly, the overall morphology of Schwann cells lacking claudin-19 expression appeared to be normal not only in the internodal region but also at the node of Ranvier, except that TJs completely disappeared, at least from the outer/inner mesaxons.These findings have indicated that, similar to epithelial cells, Schwann cells also bear claudin-based TJs, and they have also suggested that these TJs are not involved in the polarized morphogenesis but are involved in the electrophysiological "sealing" function of Schwann cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Graduate School of Medicine, Kyoto University, Japan.

ABSTRACT
Tight junction (TJ)-like structures have been reported in Schwann cells, but their molecular composition and physiological function remain elusive. We found that claudin-19, a novel member of the claudin family (TJ adhesion molecules in epithelia), constituted these structures. Claudin-19-deficient mice were generated, and they exhibited behavioral abnormalities that could be attributed to peripheral nervous system deficits. Electrophysiological analyses showed that the claudin-19 deficiency affected the nerve conduction of peripheral myelinated fibers. Interestingly, the overall morphology of Schwann cells lacking claudin-19 expression appeared to be normal not only in the internodal region but also at the node of Ranvier, except that TJs completely disappeared, at least from the outer/inner mesaxons. These findings have indicated that, similar to epithelial cells, Schwann cells also bear claudin-based TJs, and they have also suggested that these TJs are not involved in the polarized morphogenesis but are involved in the electrophysiological "sealing" function of Schwann cells.

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Overall morphology of internodal segments of peripheral myelinated axons of claudin-19–deficient mice. (A) Transverse sectional views of peripheral nerves of Cld19+/+ and Cld19−/− mice. (left) The saphenous nerves were examined by ultrathin section electron microscopy. No significant difference was discerned in the myelination between Cld19+/+ and Cld19−/− mice (see g values in the text). (right) Transverse frozen sections were cut from the sciatic nerves and were triple stained with anti–claudin-19 pAb (green), anti–myelin basic protein mAb (red), and antineurofilament pAb (blue). In the Cld19+/+ sciatic nerve, two claudin-19–positive spots were detectable in each myelinated axon, which may correspond to the outer (arrows) and inner (arrowheads) mesaxons (see Fig. 8 a). In the Cld19−/− sciatic nerve, claudin-19 appeared to be simply removed without affecting the overall morphology of myelinated axons. (B) Claudin-19 and E-cadherin in myelinated axons. Transverse frozen sections were cut from Cld19+/+ and Cld19−/− sciatic nerves and were triple stained with anti–E-cadherin mAb (red), anti–claudin-19 pAb (green), and antineurofilament pAb (blue). In each Cld19+/+ myelinated axon, claudin-19 was concentrated at one of the largest E-cadherin–positive puncta on the Schwann cell surface; i.e., outer mesaxon (arrows) as well as at inner mesaxon (arrowheads). In Cld19−/− axons, claudin-19 disappeared without affecting the distribution of E-cadherin. Bars: (A, left) 2 μm; (A, right) 5 μm; (B) 5 μm.
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fig6: Overall morphology of internodal segments of peripheral myelinated axons of claudin-19–deficient mice. (A) Transverse sectional views of peripheral nerves of Cld19+/+ and Cld19−/− mice. (left) The saphenous nerves were examined by ultrathin section electron microscopy. No significant difference was discerned in the myelination between Cld19+/+ and Cld19−/− mice (see g values in the text). (right) Transverse frozen sections were cut from the sciatic nerves and were triple stained with anti–claudin-19 pAb (green), anti–myelin basic protein mAb (red), and antineurofilament pAb (blue). In the Cld19+/+ sciatic nerve, two claudin-19–positive spots were detectable in each myelinated axon, which may correspond to the outer (arrows) and inner (arrowheads) mesaxons (see Fig. 8 a). In the Cld19−/− sciatic nerve, claudin-19 appeared to be simply removed without affecting the overall morphology of myelinated axons. (B) Claudin-19 and E-cadherin in myelinated axons. Transverse frozen sections were cut from Cld19+/+ and Cld19−/− sciatic nerves and were triple stained with anti–E-cadherin mAb (red), anti–claudin-19 pAb (green), and antineurofilament pAb (blue). In each Cld19+/+ myelinated axon, claudin-19 was concentrated at one of the largest E-cadherin–positive puncta on the Schwann cell surface; i.e., outer mesaxon (arrows) as well as at inner mesaxon (arrowheads). In Cld19−/− axons, claudin-19 disappeared without affecting the distribution of E-cadherin. Bars: (A, left) 2 μm; (A, right) 5 μm; (B) 5 μm.

Mentions: To determine which types of cells in peripheral nerves expressed claudin-19, we first attempted to raise a specific pAb in rabbits using keyhole limpet hemocyanin–conjugated peptides that corresponded to the COOH-terminal tail of claudin-19 as an antigen. One of the affinity-purified pAbs appeared to be specific for claudin-19, as examined with Western blotting against GST fusion proteins with the cytoplasmic tails of claudin-1 to -16 (Fig. 1 C). This specificity was later confirmed in the analyses of claudin-19–deficient mice (see Fig. 6).


Tight junctions in Schwann cells of peripheral myelinated axons: a lesson from claudin-19-deficient mice.

Miyamoto T, Morita K, Takemoto D, Takeuchi K, Kitano Y, Miyakawa T, Nakayama K, Okamura Y, Sasaki H, Miyachi Y, Furuse M, Tsukita S - J. Cell Biol. (2005)

Overall morphology of internodal segments of peripheral myelinated axons of claudin-19–deficient mice. (A) Transverse sectional views of peripheral nerves of Cld19+/+ and Cld19−/− mice. (left) The saphenous nerves were examined by ultrathin section electron microscopy. No significant difference was discerned in the myelination between Cld19+/+ and Cld19−/− mice (see g values in the text). (right) Transverse frozen sections were cut from the sciatic nerves and were triple stained with anti–claudin-19 pAb (green), anti–myelin basic protein mAb (red), and antineurofilament pAb (blue). In the Cld19+/+ sciatic nerve, two claudin-19–positive spots were detectable in each myelinated axon, which may correspond to the outer (arrows) and inner (arrowheads) mesaxons (see Fig. 8 a). In the Cld19−/− sciatic nerve, claudin-19 appeared to be simply removed without affecting the overall morphology of myelinated axons. (B) Claudin-19 and E-cadherin in myelinated axons. Transverse frozen sections were cut from Cld19+/+ and Cld19−/− sciatic nerves and were triple stained with anti–E-cadherin mAb (red), anti–claudin-19 pAb (green), and antineurofilament pAb (blue). In each Cld19+/+ myelinated axon, claudin-19 was concentrated at one of the largest E-cadherin–positive puncta on the Schwann cell surface; i.e., outer mesaxon (arrows) as well as at inner mesaxon (arrowheads). In Cld19−/− axons, claudin-19 disappeared without affecting the distribution of E-cadherin. Bars: (A, left) 2 μm; (A, right) 5 μm; (B) 5 μm.
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fig6: Overall morphology of internodal segments of peripheral myelinated axons of claudin-19–deficient mice. (A) Transverse sectional views of peripheral nerves of Cld19+/+ and Cld19−/− mice. (left) The saphenous nerves were examined by ultrathin section electron microscopy. No significant difference was discerned in the myelination between Cld19+/+ and Cld19−/− mice (see g values in the text). (right) Transverse frozen sections were cut from the sciatic nerves and were triple stained with anti–claudin-19 pAb (green), anti–myelin basic protein mAb (red), and antineurofilament pAb (blue). In the Cld19+/+ sciatic nerve, two claudin-19–positive spots were detectable in each myelinated axon, which may correspond to the outer (arrows) and inner (arrowheads) mesaxons (see Fig. 8 a). In the Cld19−/− sciatic nerve, claudin-19 appeared to be simply removed without affecting the overall morphology of myelinated axons. (B) Claudin-19 and E-cadherin in myelinated axons. Transverse frozen sections were cut from Cld19+/+ and Cld19−/− sciatic nerves and were triple stained with anti–E-cadherin mAb (red), anti–claudin-19 pAb (green), and antineurofilament pAb (blue). In each Cld19+/+ myelinated axon, claudin-19 was concentrated at one of the largest E-cadherin–positive puncta on the Schwann cell surface; i.e., outer mesaxon (arrows) as well as at inner mesaxon (arrowheads). In Cld19−/− axons, claudin-19 disappeared without affecting the distribution of E-cadherin. Bars: (A, left) 2 μm; (A, right) 5 μm; (B) 5 μm.
Mentions: To determine which types of cells in peripheral nerves expressed claudin-19, we first attempted to raise a specific pAb in rabbits using keyhole limpet hemocyanin–conjugated peptides that corresponded to the COOH-terminal tail of claudin-19 as an antigen. One of the affinity-purified pAbs appeared to be specific for claudin-19, as examined with Western blotting against GST fusion proteins with the cytoplasmic tails of claudin-1 to -16 (Fig. 1 C). This specificity was later confirmed in the analyses of claudin-19–deficient mice (see Fig. 6).

Bottom Line: Claudin-19-deficient mice were generated, and they exhibited behavioral abnormalities that could be attributed to peripheral nervous system deficits.Interestingly, the overall morphology of Schwann cells lacking claudin-19 expression appeared to be normal not only in the internodal region but also at the node of Ranvier, except that TJs completely disappeared, at least from the outer/inner mesaxons.These findings have indicated that, similar to epithelial cells, Schwann cells also bear claudin-based TJs, and they have also suggested that these TJs are not involved in the polarized morphogenesis but are involved in the electrophysiological "sealing" function of Schwann cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Biology, Graduate School of Medicine, Kyoto University, Japan.

ABSTRACT
Tight junction (TJ)-like structures have been reported in Schwann cells, but their molecular composition and physiological function remain elusive. We found that claudin-19, a novel member of the claudin family (TJ adhesion molecules in epithelia), constituted these structures. Claudin-19-deficient mice were generated, and they exhibited behavioral abnormalities that could be attributed to peripheral nervous system deficits. Electrophysiological analyses showed that the claudin-19 deficiency affected the nerve conduction of peripheral myelinated fibers. Interestingly, the overall morphology of Schwann cells lacking claudin-19 expression appeared to be normal not only in the internodal region but also at the node of Ranvier, except that TJs completely disappeared, at least from the outer/inner mesaxons. These findings have indicated that, similar to epithelial cells, Schwann cells also bear claudin-based TJs, and they have also suggested that these TJs are not involved in the polarized morphogenesis but are involved in the electrophysiological "sealing" function of Schwann cells.

Show MeSH
Related in: MedlinePlus