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The raft-associated protein MAL is required for maintenance of proper axon--glia interactions in the central nervous system.

Schaeren-Wiemers N, Bonnet A, Erb M, Erne B, Bartsch U, Kern F, Mantei N, Sherman D, Suter U - J. Cell Biol. (2004)

Bottom Line: These structural changes were accompanied by a marked reduction of contactin-associated protein/paranodin, neurofascin 155 (NF155), and the potassium channel Kv1.2, whereas nodal clusters of sodium channels were unaltered.Biochemical analysis revealed reduced myelin-associated glycoprotein, myelin basic protein, and NF155 protein levels in myelin and myelin-derived rafts.Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes, likely by controlling the trafficking and/or sorting of NF155 and other membrane components in oligodendrocytes.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology, Department of Research, University Hospital Basel, 4056 Basel, Switzerland. Nicole.Schaeren-Wiemers@unibas.ch

ABSTRACT
The myelin and lymphocyte protein (MAL) is a tetraspan raft-associated proteolipid predominantly expressed by oligodendrocytes and Schwann cells. We show that genetic ablation of mal resulted in cytoplasmic inclusions within compact myelin, paranodal loops that are everted away from the axon, and disorganized transverse bands at the paranode--axon interface in the adult central nervous system. These structural changes were accompanied by a marked reduction of contactin-associated protein/paranodin, neurofascin 155 (NF155), and the potassium channel Kv1.2, whereas nodal clusters of sodium channels were unaltered. Initial formation of paranodal regions appeared normal, but abnormalities became detectable when MAL started to be expressed. Biochemical analysis revealed reduced myelin-associated glycoprotein, myelin basic protein, and NF155 protein levels in myelin and myelin-derived rafts. Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes, likely by controlling the trafficking and/or sorting of NF155 and other membrane components in oligodendrocytes.

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Mal-deficient mice exhibit paranodal abnormalities. EM analysis of longitudinally sectioned optic nerves from adult KO mice revealed numerous disorganized paranodes with everted paranodal loops not adhering to the axon (B, D, E; arrow in B). In WT animals, normal paranodal loop organization was observed (A and C). Transverse bands were regularly detected in WT mice (C, arrowheads), whereas in KO mice transverse bands were usually present but less organized (D and E, arrowheads), or absent under some of the paranodal loops (D, arrow). In the paranode in D, there is only one loop with normal septate-like junctions (arrowheads), whereas the adjacent loops lack intact septa. Analysis of longitudinal sections of optic nerves from P20 WT mice (F) revealed intact paranodes with normal transverse bands (F, arrowheads). Optic nerves of age-matched KO (G), in contrast, contained numerous disorganized paranodes with everted paranodal loops and irregular transverse bands (G, arrowheads). Bars: A, 1 μm; B, 0.5 μm; C, 0.2 μm; D, 0.2 μm; E, 0.25 μm; F and G, 0.1 μm.
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fig4: Mal-deficient mice exhibit paranodal abnormalities. EM analysis of longitudinally sectioned optic nerves from adult KO mice revealed numerous disorganized paranodes with everted paranodal loops not adhering to the axon (B, D, E; arrow in B). In WT animals, normal paranodal loop organization was observed (A and C). Transverse bands were regularly detected in WT mice (C, arrowheads), whereas in KO mice transverse bands were usually present but less organized (D and E, arrowheads), or absent under some of the paranodal loops (D, arrow). In the paranode in D, there is only one loop with normal septate-like junctions (arrowheads), whereas the adjacent loops lack intact septa. Analysis of longitudinal sections of optic nerves from P20 WT mice (F) revealed intact paranodes with normal transverse bands (F, arrowheads). Optic nerves of age-matched KO (G), in contrast, contained numerous disorganized paranodes with everted paranodal loops and irregular transverse bands (G, arrowheads). Bars: A, 1 μm; B, 0.5 μm; C, 0.2 μm; D, 0.2 μm; E, 0.25 μm; F and G, 0.1 μm.

Mentions: Detailed analysis of longitudinal sections of optic nerves from KO mice revealed a large number of abnormal paranodes, with everted paranodal loops projecting away instead of contacting the axon (Fig. 4). Examination of 94 paranodes from two KO animals (3-mo-old) revealed detached and inversely oriented paranodal loops in the majority of the cases (83 of 94; Fig. 4, B, D, and E), whereas in WT animals (Fig. 4, A and C) everted loops were only observed in 2 of 132 analyzed paranodes (unpublished data). Transverse bands, the hallmark of the paranodal axoglia junction of WT nerves (Fig. 4 C, arrowheads), were less regularly organized in KO mice and consisted of diffuse electron-dense material instead of septa (Fig. 4, D and E; arrowheads). Moreover, septa-like structures were frequently absent under some paranodal loops in KO mice (Fig. 4 D, arrow). In very few KO paranodes, transverse bands were still present and had a normal morphology (unpublished data). These analyses demonstrate that although transverse bands were not completely absent in KO animals, they were disrupted and not discretely organized. In contrast to adult KO, which exhibited paranodal abnormalities in 88% of the sites examined, analysis of optic nerves from 20-d-old KO showed everted paranodal loops in only ∼50% of the cases (Fig. 4 G), suggesting that the paranodal junctions were formed normally during development and then disassembled.


The raft-associated protein MAL is required for maintenance of proper axon--glia interactions in the central nervous system.

Schaeren-Wiemers N, Bonnet A, Erb M, Erne B, Bartsch U, Kern F, Mantei N, Sherman D, Suter U - J. Cell Biol. (2004)

Mal-deficient mice exhibit paranodal abnormalities. EM analysis of longitudinally sectioned optic nerves from adult KO mice revealed numerous disorganized paranodes with everted paranodal loops not adhering to the axon (B, D, E; arrow in B). In WT animals, normal paranodal loop organization was observed (A and C). Transverse bands were regularly detected in WT mice (C, arrowheads), whereas in KO mice transverse bands were usually present but less organized (D and E, arrowheads), or absent under some of the paranodal loops (D, arrow). In the paranode in D, there is only one loop with normal septate-like junctions (arrowheads), whereas the adjacent loops lack intact septa. Analysis of longitudinal sections of optic nerves from P20 WT mice (F) revealed intact paranodes with normal transverse bands (F, arrowheads). Optic nerves of age-matched KO (G), in contrast, contained numerous disorganized paranodes with everted paranodal loops and irregular transverse bands (G, arrowheads). Bars: A, 1 μm; B, 0.5 μm; C, 0.2 μm; D, 0.2 μm; E, 0.25 μm; F and G, 0.1 μm.
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Related In: Results  -  Collection

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fig4: Mal-deficient mice exhibit paranodal abnormalities. EM analysis of longitudinally sectioned optic nerves from adult KO mice revealed numerous disorganized paranodes with everted paranodal loops not adhering to the axon (B, D, E; arrow in B). In WT animals, normal paranodal loop organization was observed (A and C). Transverse bands were regularly detected in WT mice (C, arrowheads), whereas in KO mice transverse bands were usually present but less organized (D and E, arrowheads), or absent under some of the paranodal loops (D, arrow). In the paranode in D, there is only one loop with normal septate-like junctions (arrowheads), whereas the adjacent loops lack intact septa. Analysis of longitudinal sections of optic nerves from P20 WT mice (F) revealed intact paranodes with normal transverse bands (F, arrowheads). Optic nerves of age-matched KO (G), in contrast, contained numerous disorganized paranodes with everted paranodal loops and irregular transverse bands (G, arrowheads). Bars: A, 1 μm; B, 0.5 μm; C, 0.2 μm; D, 0.2 μm; E, 0.25 μm; F and G, 0.1 μm.
Mentions: Detailed analysis of longitudinal sections of optic nerves from KO mice revealed a large number of abnormal paranodes, with everted paranodal loops projecting away instead of contacting the axon (Fig. 4). Examination of 94 paranodes from two KO animals (3-mo-old) revealed detached and inversely oriented paranodal loops in the majority of the cases (83 of 94; Fig. 4, B, D, and E), whereas in WT animals (Fig. 4, A and C) everted loops were only observed in 2 of 132 analyzed paranodes (unpublished data). Transverse bands, the hallmark of the paranodal axoglia junction of WT nerves (Fig. 4 C, arrowheads), were less regularly organized in KO mice and consisted of diffuse electron-dense material instead of septa (Fig. 4, D and E; arrowheads). Moreover, septa-like structures were frequently absent under some paranodal loops in KO mice (Fig. 4 D, arrow). In very few KO paranodes, transverse bands were still present and had a normal morphology (unpublished data). These analyses demonstrate that although transverse bands were not completely absent in KO animals, they were disrupted and not discretely organized. In contrast to adult KO, which exhibited paranodal abnormalities in 88% of the sites examined, analysis of optic nerves from 20-d-old KO showed everted paranodal loops in only ∼50% of the cases (Fig. 4 G), suggesting that the paranodal junctions were formed normally during development and then disassembled.

Bottom Line: These structural changes were accompanied by a marked reduction of contactin-associated protein/paranodin, neurofascin 155 (NF155), and the potassium channel Kv1.2, whereas nodal clusters of sodium channels were unaltered.Biochemical analysis revealed reduced myelin-associated glycoprotein, myelin basic protein, and NF155 protein levels in myelin and myelin-derived rafts.Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes, likely by controlling the trafficking and/or sorting of NF155 and other membrane components in oligodendrocytes.

View Article: PubMed Central - PubMed

Affiliation: Neurobiology, Department of Research, University Hospital Basel, 4056 Basel, Switzerland. Nicole.Schaeren-Wiemers@unibas.ch

ABSTRACT
The myelin and lymphocyte protein (MAL) is a tetraspan raft-associated proteolipid predominantly expressed by oligodendrocytes and Schwann cells. We show that genetic ablation of mal resulted in cytoplasmic inclusions within compact myelin, paranodal loops that are everted away from the axon, and disorganized transverse bands at the paranode--axon interface in the adult central nervous system. These structural changes were accompanied by a marked reduction of contactin-associated protein/paranodin, neurofascin 155 (NF155), and the potassium channel Kv1.2, whereas nodal clusters of sodium channels were unaltered. Initial formation of paranodal regions appeared normal, but abnormalities became detectable when MAL started to be expressed. Biochemical analysis revealed reduced myelin-associated glycoprotein, myelin basic protein, and NF155 protein levels in myelin and myelin-derived rafts. Our results demonstrate a critical role for MAL in the maintenance of central nervous system paranodes, likely by controlling the trafficking and/or sorting of NF155 and other membrane components in oligodendrocytes.

Show MeSH
Related in: MedlinePlus