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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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Cytoplasmic inclusions in compact CNS myelin of mal KO mice. EM analysis of optic nerves from WT and age-matched KO mice in adult (A–D) and during development (E and F). (A) Myelin sheaths in WT mice lack oligodendrocytic cytoplasmic inclusions in compact myelin, and the majority of sheaths display a well-developed periaxonal cytoplasmic collar that spans more than half of the axonal circumference. In mal KO, in contrast, many axons (ax1–ax14 in B; ax1–ax3 in C; ax4 in D) are surrounded by sheaths that contain cytoplasmic inclusions in compact myelin. Most sheaths lack a well-developed periaxonal cytoplasmic collar (B–D). Close inspection of KO sheaths at higher magnification suggests that some cytoplasmic inclusions are indicative of the presence of two myelin sheaths concentrically surrounding the same axon. Inner and outer sheaths are either spiraling in opposite directions (ax1 and ax2 in C; ax4 in D) or in the same direction (ax3 in C). (C and D) 1 and 3 indicate the inner tongue process of the inner and outer myelin sheath, respectively; 2 and 4 indicate the external tongue process of the inner and outer myelin sheath, respectively. (E and F) EM analysis of optic nerve during development at P20. Note the similar extent of myelination in WT and KO mice. Inclusions of cytoplasm within the compact myelin of KO mice were frequent at P20 (F, arrows). Although myelination in KO mice appeared less homogenous, no difference in myelin sheath thickness or in number of myelinated fibers was observed between genotypes. Bars: A, 0.5 μm; B, E, and F, 1 μm; C and D, 0.2 μm.
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fig3: Cytoplasmic inclusions in compact CNS myelin of mal KO mice. EM analysis of optic nerves from WT and age-matched KO mice in adult (A–D) and during development (E and F). (A) Myelin sheaths in WT mice lack oligodendrocytic cytoplasmic inclusions in compact myelin, and the majority of sheaths display a well-developed periaxonal cytoplasmic collar that spans more than half of the axonal circumference. In mal KO, in contrast, many axons (ax1–ax14 in B; ax1–ax3 in C; ax4 in D) are surrounded by sheaths that contain cytoplasmic inclusions in compact myelin. Most sheaths lack a well-developed periaxonal cytoplasmic collar (B–D). Close inspection of KO sheaths at higher magnification suggests that some cytoplasmic inclusions are indicative of the presence of two myelin sheaths concentrically surrounding the same axon. Inner and outer sheaths are either spiraling in opposite directions (ax1 and ax2 in C; ax4 in D) or in the same direction (ax3 in C). (C and D) 1 and 3 indicate the inner tongue process of the inner and outer myelin sheath, respectively; 2 and 4 indicate the external tongue process of the inner and outer myelin sheath, respectively. (E and F) EM analysis of optic nerve during development at P20. Note the similar extent of myelination in WT and KO mice. Inclusions of cytoplasm within the compact myelin of KO mice were frequent at P20 (F, arrows). Although myelination in KO mice appeared less homogenous, no difference in myelin sheath thickness or in number of myelinated fibers was observed between genotypes. Bars: A, 0.5 μm; B, E, and F, 1 μm; C and D, 0.2 μm.

Mentions: High levels of MAL protein were found in all myelinated fiber tracts including the optic nerve (Fig. 1 B). EM analysis of optic nerves from 2-mo-old mal KO mice revealed that although the majority of myelin sheaths were normal with respect to myelin sheath thickness, fiber diameter, and g-ratio (unpublished data), KO animals differed from control animals in the amount of cytoplasm within the myelin sheath (Fig. 3 B). In KO animals, oligodendrocyte cytoplasm was not restricted to the inner and external tongue processes as in WT mice, but conspicuous cytoplasmic inclusions were also present within compact myelin (Fig. 3, compare A with B). In some cases, these cytoplasmic inclusions appeared to correspond to terminal oligodendrocyte processes as their presence correlated with a change in the spiraling direction of myelin. Thus, some axons in KO mice appeared to be concentrically surrounded by more than one myelin sheath (Fig. 3, C and D). For quantification, we analyzed ultrathin sections of optic nerves from 2-mo-old KO and WT mice in double-blind experiments (four KO and three WT mice). Approximately 300 randomly selected myelin sheaths from each animal were monitored for the presence of cytoplasmic inclusions in compact myelin. Cytoplasmic domains were found in 11% (± 1.9%) of all analyzed sheaths of KO animals, but were virtually absent (0.5 ± 0.3%) from control animals. Furthermore, most myelin sheaths in optic nerves of KO mice lacked a well-developed periaxonal oligodendrocyte cytoplasmic collar (Fig. 3, B–D), whereas the majority of myelin sheaths in WT mice had a periaxonal cytoplasmic collar that spanned more than half of the axonal circumference (Fig. 3 A). Our results show that MAL deficiency leads to the formation of morphologically aberrant myelin sheaths, suggesting impaired axon–glia as well as glia–glia interactions.


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)

Cytoplasmic inclusions in compact CNS myelin of mal KO mice. EM analysis of optic nerves from WT and age-matched KO mice in adult (A–D) and during development (E and F). (A) Myelin sheaths in WT mice lack oligodendrocytic cytoplasmic inclusions in compact myelin, and the majority of sheaths display a well-developed periaxonal cytoplasmic collar that spans more than half of the axonal circumference. In mal KO, in contrast, many axons (ax1–ax14 in B; ax1–ax3 in C; ax4 in D) are surrounded by sheaths that contain cytoplasmic inclusions in compact myelin. Most sheaths lack a well-developed periaxonal cytoplasmic collar (B–D). Close inspection of KO sheaths at higher magnification suggests that some cytoplasmic inclusions are indicative of the presence of two myelin sheaths concentrically surrounding the same axon. Inner and outer sheaths are either spiraling in opposite directions (ax1 and ax2 in C; ax4 in D) or in the same direction (ax3 in C). (C and D) 1 and 3 indicate the inner tongue process of the inner and outer myelin sheath, respectively; 2 and 4 indicate the external tongue process of the inner and outer myelin sheath, respectively. (E and F) EM analysis of optic nerve during development at P20. Note the similar extent of myelination in WT and KO mice. Inclusions of cytoplasm within the compact myelin of KO mice were frequent at P20 (F, arrows). Although myelination in KO mice appeared less homogenous, no difference in myelin sheath thickness or in number of myelinated fibers was observed between genotypes. Bars: A, 0.5 μm; B, E, and F, 1 μm; C and D, 0.2 μm.
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fig3: Cytoplasmic inclusions in compact CNS myelin of mal KO mice. EM analysis of optic nerves from WT and age-matched KO mice in adult (A–D) and during development (E and F). (A) Myelin sheaths in WT mice lack oligodendrocytic cytoplasmic inclusions in compact myelin, and the majority of sheaths display a well-developed periaxonal cytoplasmic collar that spans more than half of the axonal circumference. In mal KO, in contrast, many axons (ax1–ax14 in B; ax1–ax3 in C; ax4 in D) are surrounded by sheaths that contain cytoplasmic inclusions in compact myelin. Most sheaths lack a well-developed periaxonal cytoplasmic collar (B–D). Close inspection of KO sheaths at higher magnification suggests that some cytoplasmic inclusions are indicative of the presence of two myelin sheaths concentrically surrounding the same axon. Inner and outer sheaths are either spiraling in opposite directions (ax1 and ax2 in C; ax4 in D) or in the same direction (ax3 in C). (C and D) 1 and 3 indicate the inner tongue process of the inner and outer myelin sheath, respectively; 2 and 4 indicate the external tongue process of the inner and outer myelin sheath, respectively. (E and F) EM analysis of optic nerve during development at P20. Note the similar extent of myelination in WT and KO mice. Inclusions of cytoplasm within the compact myelin of KO mice were frequent at P20 (F, arrows). Although myelination in KO mice appeared less homogenous, no difference in myelin sheath thickness or in number of myelinated fibers was observed between genotypes. Bars: A, 0.5 μm; B, E, and F, 1 μm; C and D, 0.2 μm.
Mentions: High levels of MAL protein were found in all myelinated fiber tracts including the optic nerve (Fig. 1 B). EM analysis of optic nerves from 2-mo-old mal KO mice revealed that although the majority of myelin sheaths were normal with respect to myelin sheath thickness, fiber diameter, and g-ratio (unpublished data), KO animals differed from control animals in the amount of cytoplasm within the myelin sheath (Fig. 3 B). In KO animals, oligodendrocyte cytoplasm was not restricted to the inner and external tongue processes as in WT mice, but conspicuous cytoplasmic inclusions were also present within compact myelin (Fig. 3, compare A with B). In some cases, these cytoplasmic inclusions appeared to correspond to terminal oligodendrocyte processes as their presence correlated with a change in the spiraling direction of myelin. Thus, some axons in KO mice appeared to be concentrically surrounded by more than one myelin sheath (Fig. 3, C and D). For quantification, we analyzed ultrathin sections of optic nerves from 2-mo-old KO and WT mice in double-blind experiments (four KO and three WT mice). Approximately 300 randomly selected myelin sheaths from each animal were monitored for the presence of cytoplasmic inclusions in compact myelin. Cytoplasmic domains were found in 11% (± 1.9%) of all analyzed sheaths of KO animals, but were virtually absent (0.5 ± 0.3%) from control animals. Furthermore, most myelin sheaths in optic nerves of KO mice lacked a well-developed periaxonal oligodendrocyte cytoplasmic collar (Fig. 3, B–D), whereas the majority of myelin sheaths in WT mice had a periaxonal cytoplasmic collar that spanned more than half of the axonal circumference (Fig. 3 A). Our results show that MAL deficiency leads to the formation of morphologically aberrant myelin sheaths, suggesting impaired axon–glia as well as glia–glia interactions.

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