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Keywords:

  • Myelin oligodendrocyte glycoprotein;
  • Myelin;
  • Marsupial;
  • C1q;
  • Galactocerebroside;
  • Microtubule

Abstract

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Abstract : Myelin oligodendrocyte glycoprotein (MOG) is a quantitatively minor component of CNS myelin whose function remains relatively unknown. As MOG is an autoantigen capable of producing a demyelinating multiple sclerosis-like disease in mice and rats, much of the research directed toward MOG has been immunological in nature. Although the function of MOG is yet to be elucidated, there is now a relatively large amount of biochemical and molecular data relating to MOG. Here we summarize this information and include our recent findings pertaining to the cloning of the marsupial MOG gene. On the basis of this knowledge we suggest three possible functions for MOG : (a) a cellular adhesive molecule, (b) a regulator of oligodendrocyte microtubule stability, and (c) a mediator of interactions between myelin and the immune system, in particular, the complement cascade. Given that antibodies to MOG and to the myelin-specific glycolipid galactocerebroside (Gal-C) both activate the same signaling pathway leading to MBP degradation, we propose that there is a direct interaction between the membrane-associated regions of MOG and Gal-C. Such an interaction may have important consequences regarding the membrane topology and function of both molecules. Finally, we examine how polymorphisms and/or mutations to the MOG gene could contribute to the pathogenesis of multiple sclerosis.

Myelin is the multilamellar sheath necessary for saltatory conduction in nerves and is formed by the elaboration of oligodendrocyte processes around axons (Dubois-Dalcq and Armstrong, 1990). The formation of myelin is dependent on the expression of several myelin-specific proteins, such as myelin basic protein (MBP), myelin-associated glycoprotein, proteolipid protein (PLP), and 2′, 3′-cyclic nucleotide 3′-phosphodiesterase (Dubois-Dalcq and Armstrong, 1990). Myelin also contains several quantitatively minor glycoproteins whose function remains relatively unknown (Quarles, 1997). One such glycoprotein is myelin oligodendrocyte glycoprotein (MOG). The cloning of MOG from several species (Gardinier et al., 1992 ; Pham-Dinh et al., 1993 ; Hilton et al., 1995) has revealed its structure, but the function(s) of MOG in myelin remains largely unknown. Indeed, as recently reviewed by our laboratory (Bernard et al., 1997), it is the identification of MOG as an important autoantigen in demyelinating diseases, rather than its functional considerations, that has provoked most of the recent research. Furthermore, the difficulties associated with the purification of native MOG has also hindered research into the function of MOG (for a discussion of this problem, see Bettadapura et al., 1998). This review summarizes the known molecular and biochemical characteristics of MOG (Table 1) and uses this information to examine possible functions for MOG.

Table 1. Biochemical properties of MOG
CNS myelin-specific
Located on the outermost lamellae of the myelin sheath and on the surface of oligodendrocytes
Surface marker of oligodendrocyte maturation
Expression parallels myelination
Quantitatively minor component of myelin (0.05%)
Molecular size of 28 kDa on sodium dodecyl sulfate-polyacrylamide gel electrophoresis
N-linked glycosylation at position 31
Highly conserved between species
Maps to the MHC region in the mouse, rat, and human
Produces demyelinating relapsing disease in mice and rats (for review, see Bernard et al., 1997)

BIOCHEMISTRY OF MOG

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Lebar et al., (1976) were the first to propose that the demyelination observed in animals injected with whole CNS homogenate was mediated by immune responses to a myelin component then termed M2, rather than to other encephalitogenic myelin proteins, such as MBP and PLP. Based on tissue and cellular localization, molecular weight, and immune cross-reactivity, M2 has been shown to be identical to MOG (Linington et al., 1984). MOG was first identified by the mouse monoclonal antibody, 8-18C5, which was produced following immunization with rat cerebellar glycoproteins (Linington et al., 1984). The epitope interacting with the 8-18C5 antibody is conserved in mouse, rat, guinea pig, bovine, monkey, and human MOG but is absent in avian and reptile brains, suggesting that MOG is not found in these species (Slavin et al., 1997). The 8-18C5 antibody has been used extensively in immunohistochemical, immune, and biochemical studies of MOG ; however, the epitope recognized by this antibody has not yet been elucidated. Using recombinant MOG, we have determined that the 8-18C5 epitope is contained within the Ig-like domain (Bettadapura et al., 1998), but our attempts to refine further the 8-18C5 binding site have been unsuccessful. Compared with most other MOG-specific antibodies, 8-18C5 shows relatively poor reactivity to the dimeric form of MOG, suggesting that dimerization partially masks the epitope. It is likely that the 8-18C5 epitope is conformational based on the following observations : (a) The use of reducing conditions in immunoblotting dramatically reduces 8-18C5 reactivity ; (b) 8-18C5 does not bind to any peptide derived from the Ig-like region ; and (c) screening of phage random peptide libraries with 8-18C5 has not identified any peptides homologous to the MOG sequence (J. Bettadapura, H. Reid, and C. C. A. Bernard, unpublished data). Given that the 8-18C5 antibody appears to mimic the potential ligand for MOG (see below) and its possible proximity to the dimer-forming domain, more detailed mapping of the epitope could reveal significant information concerning the function of MOG.

Ultrastructural immunocytochemistry using the 8-18C5 antibody showed that MOG is preferentially expressed at the extracellular surface of the myelin sheath and oligodendrocyte processes, with only low expression in the lamellae of compact myelin and the myelin/axon border (Brunner et al., 1989 ; Scolding et al., 1989a). Immunocytochemical studies of cultured oligodendrocytes demonstrated that the expression of MOG is delayed 24—48 h compared with other major myelin proteins (Scolding et al., 1989a ; Solly et al., 1996). This observation, together with its expression on the surface of oligodendrocytes, makes MOG an excellent marker for mature oligodendrocytes. As for MBP and PLP, MOG shows a caudorostral gradient of expression throughout development, at both the mRNA (Pham-Dinh et al., 1993 ; Solly et al., 1996) and the protein (Birling et al., 1993 ; Slavin et al., 1997) level. Indeed, using immunoblotting we first detected MOG in the rat spinal cord at 10 days of age (postnatal day 10) but in the brain only at postnatal day 17 (Slavin et al., 1997). We have also analyzed the expression of MOG, MBP, and PLP in a novel hypomyelinating mouse mutant (Slavin et al., 1997). Compared with control littermates, the appearance of all three myelin proteins was delayed and reduced in an identical manner, suggesting that the general mechanisms regulating the expression of MBP and PLP are also pertinent to MOG.

The literature contains various reports for the molecular size of MOG. Initially, rat MOG was reported to be a 51-kDa protein that degraded to 20—26-kDa products (Linington et al., 1984). Later, murine MOG was reported to be a 26/28-kDa doublet, resulting from differential glycosylation of a 25-kDa protein that could dimerize to a 54-kDa product (Amiguet et al., 1992). This doublet appears specific to the mouse as it is not observed in any other species (Slavin et al., 1997). We reported that purified human MOG contained two major bands of 28 and 55 kDa, with a third minor band of 36 kDa (Abo et al., 1993 ; Slavin et al., 1997). The N-terminal sequence of the two major bands was identical (Abo et al., 1993), further supporting the hypothesis that the higher-molecular-mass band is a dimer of MOG. Similar results to that of human MOG were obtained by Birling et al. (1993) using purified bovine MOG. Both these studies confirmed that MOG is a quantitatively minor component of myelin representing some 0.05—0.1% of the total myelin protein. Recently, we showed that the highly purified recombinant Ig-like domain of MOG could also form dimers (Bettadapura et al., 1998), demonstrating that the dimer-forming domain of MOG is contained within this region. We have also observed the presence of several other MOG-immunoreactive bands of 40, 43, 48, and 78 kDa (Slavin et al., 1997), suggesting that MOG, like most myelin proteins, may exist in multiple isoforms. Indeed, the existence of multiple MOG mRNA splice variants in the human brain has been reported by several researchers (see below). If translated, however, these hypothetical proteins would be too small to account for the alternative MOG bands that have been visualized (Slavin et al., 1997). However, it is possible that dimerization of these potential proteins could contribute to the different immunoreactive MOG bands. Finally, given that murine MOG undergoes alternative glycosylation (Slavin et al., 1997), it is possible that differential glycosylation may contribute to the diversity of MOG bands seen using immunoblotting in other species, although there is no evidence to support such a proposal.

As indicated above, MOG is a glycoprotein. Analysis of the N-linked oligosaccharide structures from MOG indicated that 80% of these were of the complex type (Burger et al., 1993). A subpopulation of MOG molecules expressed the L2/HNK-1 carbohydrate epitope. This epitope has been reported on three other myelin proteins, including MAG, P0, and oligodendrocyte-myelin glycoprotein (Burger et al., 1992), but in contrast to MAG and P0, the L2/HNK-1 epitope found on MOG was expressed on all glycoprotein fractions and not just fucosylated structures (Burger et al., 1993). As the L2/HNK-1 epitope is involved in cell-to-cell interactions, it could be an indicator for the possible function of MOG (see below).

Cloning of MOG cDNA

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

The cloning of mouse, rat, bovine, and human MOG cDNA (Gardinier et al., 1992 ; Pham-Dinh et al., 1993 ; Hilton et al., 1995) revealed that the mature MOG protein is a 218-amino acid member of the Ig superfamily and is highly homologous (~90%) between species (Fig. 1A). MOG from all species also contains a 29-amino acid signal peptide (human peptide, MASLSRPSLPSCLCSFLLLLLLQVSSSYA), although, typical of such peptides, the homology between species is much lower than that observed in the mature protein (Hilton et al., 1995). Northern blot analysis of mRNA from various mouse tissues confirmed that MOG transcripts were restricted to the brain (Gardinier et al., 1992). MOG is an unusual member of this family in that it contains two putative transmembrane regions, suggesting that the C-terminal tail is also extracellular. A more recent report, however, indicated that the C-terminal portion of MOG may well be intracellular, implying that the second hydrophobic domain is associated with the membrane rather than spanning it (Kroepfl et al., 1996). Although the cDNA for rat MOG appeared to lack conventional polyadenylation signals (Gardinier et al., 1992), they are present in both the mouse and human gene (Daubas et al., 1994 ; Hilton et al., 1995). As indicated by the biochemical studies, the MOG protein contains an N-glycosylation site at amino acid 31. There is also a putative phosphorylation site at the intracellular Thr found at position 167, but this has not been confirmed experimentally.

image

Figure 1. A : Comparison of the MOG protein sequence from different species. Dashes indicate conservation of the amino acid sequence compared with the human sequence. Lines indicate the two hydrophobic domains. For ease of comparison the signal peptide sequence has been omitted. B : Comparison of the MOG protein sequence from human and eastern quoll (an Australia marsupial).

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Marsupial MOG cDNA

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Marsupials have a gestation time similar to that of rabbits (~30 days), but they are born in an embryonic state. Indeed, the period of brain growth, as well as most of the neural development, occurs after birth during the 200 days that the marsupial spends in the pouch. Myelination does not take place until postnatal day 40 and is prolonged compared with other mammals (Dunlop et al., 1988). Despite this extreme immaturity at birth, the newborn marsupial shows admirable motor competence as it makes its journey to the pouch shortly after birth. How this journey is achieved is not clearly understood, particularly because locomotion ceases as the young attaches to the teat inside the pouch. Given these differences in the developmental process, we postulate that the myelinogenesis process may also vary in the marsupial. Indeed, we have detected the presence of an extra MBP exon not seen in other mammals (Kerlero de Rosbo et al., 1993). Consequently, we determined the MOG cDNA sequence from the eastern quoll, an Australian marsupial. A comparison of this sequence with human MOG reveals that the high level of conservation seen in other species is also found in marsupials (Fig. 1B). In fact, 86% of the amino acids are identical, and many of the substitutions observed are very conservative. Like MOG from other species, the greatest area of diversity is found in the first transmembrane region, further suggesting that this region of MOG has little functional significance. The second membrane-associated domain and the C-terminal tail of marsupial and human MOG are highly conserved. This is consistent with the MOG protein from other species, although there are four substitutions not seen in other mammals. However, these substitutions are relatively conserved and probably would not significantly alter the presumed interactions between this region of MOG and other components of the myelin. On the basis of these observations we suggest that the function of MOG appears to be completely conserved in marsupials despite the developmental differences.

Genomic organization of MOG

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

The genomic organization of human and mouse MOG is very similar (Daubas et al., 1994 ; Hilton et al., 1995), although recent analysis of the human gene revealed two new alternative exons in human MOG located in regions previously considered introns (see below). However, the dominant MOG transcript is encoded by eight homologous exons in both the human and the mouse with complete conservation of the intron—exon junctions (Daubas et al., 1994 ; Hilton et al., 1995). Furthermore, the similar size of the genes, 11.1 kb in the human and 12.5 kb in the mouse, indicates a high level of similarity in intron length. The Ig-like region of MOG is encoded by exon 2 and is homologous to the Ig-like domain of butyrophilin (46% identity), the major glycoprotein found in milk fat globules (Mather and Lucinda, 1993). Expression of butyrophilin is exclusively associated with lactation, where it is presumed to have a role in milk secretion, and does not occur in myelin. Thus, it is likely that this homology occurred through exon shuffling, a process by which a common ancestral Ig-like domain becomes associated with other unrelated functional exons (Pham-Dinh et al., 1993). Indeed, the homology between MOG and butyrophilin does not extend to the functionally important transmembrane and cytoplasmic regions (Pham-Dinh et al., 1993). Exon 2 of MOG is also similar to the Ig-like domain of the chicken B-G antigens (Gardinier et al., 1992 ; Pham-Dinh et al., 1993), but whether this is another example of exon shuffling is not clear.

MOG splice variants

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Initial studies on mouse and rat MOG cDNAs provided no evidence for MOG splice variants (Gardinier et al., 1992 ; Daubas et al., 1994). Our analysis of human MOG cDNA, however, revealed a novel truncated cDNA variant that contained the Ig-like domain but only the first transmembrane region (Hilton et al., 1995). This isoform was not the result of alternative exon splicing, but rather the failure to splice out the fifth intron, which introduced an in-frame stop codon (Hilton et al., 1995). Using PCR, a total of seven splice variants has now been identified in adult human CNS tissue, but they do not appear to exist in the mouse (Ballenthin and Gardinier, 1996). It is interesting that all these splice variants affect the C-terminal tail of MOG, which is highly conserved between species. Analysis of these splicing events demonstrated that they are contained within the intron/exon boundaries previously identified by us (Hilton et al., 1995). Nevertheless, these splice variants did reveal two new exons contained within regions previously reported as introns and an additional 3′ splice acceptor site within MOG's last exon (Ballenthin and Gardinier, 1996). The revised structure for the human MOG gene is shown in Fig. 2. All the mRNA splice variants contain exon 1 (signal peptide), exon 2 (Ig-like domain), exon 4 (first transmembrane domain), and the small exons 5 and 6 (cytoplasmic region). However, inclusion of exon 3 in two of the splice variants would cause premature termination of the protein due to the presence of several in-frame stop codons, resulting in two putative MOG isoforms identical in amino acid sequence. Furthermore, both these proteins should be soluble as neither transmembrane region would be translated. The presence of exons 7, 8, 9, and 10a differs among splice variants, although the terminal 10b exon is found in all transcripts. Those variants lacking exon 8 would not contain the second membrane-associated domain. Including the original MOG transcript, these splice variants have the potential to produce seven different isoforms of MOG, one of which is soluble, four of which contain a single transmembrane domain but differ in their cytoplasmic region, and two that contain both membrane-associated regions but also differ in their C-terminal region. Apart from the original MOG protein, none of these isoforms has been detected at the protein level, suggesting that they are not translated or are translated at extremely low levels and thus not detectable by immunoblotting. As suggested previously, the MOG immunoreactivity observed by us in the range of 40—48 kDa (Slavin et al., 1997) may represent a series of heterodimers among the different isoforms, but we have not detected any of the MOG monomers that would be expected from these splice variants. The use of highly specific isoform antisera and better analytical techniques, such as two-dimensional gel analysis, may help resolve this issue. Also, a detailed examination of CSF, rather than myelin, may reveal the presence of soluble MOG.

image

Figure 2. Intron—exon structure of human genomic MOG. All transcripts contain exons 1, 2, 4, 5, 6, and 10b. Inclusion of exon 3 in some transcripts produces a truncated form of MOG, which would be soluble. Alternative transcripts also occur owing to the presence or absence of exons 7, 8, 9, and 10a. The only MOG isoform so far detected at the protein level contains exons 1, 2, 4-6, 8, 9, 10a, and 10b.

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MOG promoter region

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

As MOG is found exclusively in oligodendrocytes, its promoter region must contain elements that tightly control this cell-specific expression. Therefore, detailed analysis of the MOG promoter could lead to the identification of novel transcription factors important in regulating the expression of oligodendrocyte-specific proteins. Daubas et al. (1994) reported the sequence of the putative promoter region of the mouse MOG gene. The probable TATA and CAAT boxes are observed at positions—50 and—101, respectively. Several putative binding sites for transcription factors are also found within a 480-bp region upstream of the cap site (Daubas et al., 1994), including four motifs homologous to consensus sequences found in other myelin-specific proteins. Three of the sequences, TTGGTCACAATAAG (—476), GGGAAAAGA (—206), and GGACATGCAGCCG (+23), are 64—80% homologous to regions in the PLP gene known to bind nuclear factors (Berndt et al., 1992). The motif found at position —476 is also found in P0 and MBP (Berndt et al., 1992). The fourth motif, ATGGAGGGGA (—211), is 80% homologous to the FP12 motif found in PLP and MBP genes from several species (Nave and Lemke, 1991). In vitro mutagenesis has shown that this region is critical for high expression from the PLP promoter, but its significance in the MOG promoter has yet to be demonstrated (Nave and Lemke, 1991).

Recently, Solly et al. (1997) reported a functional analysis of the mouse MOG gene promoter in the CG4 oligodendroglial cell line. Basal expression of a luciferase reporter gene was obtained using a region of the MOG promoter encompassing —188 to —19 (Solly et al., 1997). As indicated above, this region contains the obligatory TATA and CAAT boxes. It is interesting that this region is also required for oligodendroglial-specific transcription and thus must contain an oligodendroglial-specific element, although this potential novel motif has not been identified. A threefold increase in luciferase activity was reported when regions between —435 and —657 were included in the promoter construct (Solly et al., 1997). It is significant that this region does not contain the three purine-rich cis regulatory elements thought to be important for the optimal expression of other myelin proteins, including MBP, PLP, 2′, 3′-cyclic nucleotide 3′-phosphodiesterase, myelin-associated glycoprotein, and P0 (Hudson et al., 1995). Therefore, these elements are unlikely to account for the maximal expression of the MOG gene, once again suggesting the presence of novel motifs within this region of the promoter. Finally, several regions upstream of —657 were shown to inhibit the expression of MOG (Solly et al., 1997). Potential binding sites for several well-characterized transcription repressors, including GTX, MyEF-2, and SCIP, are contained within this portion of the promoter sequence.

Chromosomal location of MOG

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Pham-Dinh et al. (1993) localized the human MOG gene to the major histocompatibility complex (MHC) on chromosome 6p21.3-p22. The same authors also reported that mouse MOG mapped to band C of chromosome 17, a region homologous to the human MHC. It is interesting that the butyrophilin gene colocalized to the same region, further supporting the contention that their shared Ig-like domains probably arose through exon shuffling (Pham-Dinh et al., 1993). A more detailed mapping of the MOG gene revealed that it is located 60 kb telomeric to HLA-F in a head-to-head orientation (Pham-Dinh et al., 1995).

MOG as an adhesion molecule

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

The homology between the Ig-like domain of MOG and similar domains in butyrophilin and the chicken B-G antigens has failed to identify a function of MOG. On the other hand, the surface location of MOG (Scolding et al., 1989a), its identification as a member of the Ig superfamily (Gardinier et al., 1992), and the presence of an L2/HNK-1 carbohydrate epitope (Burger et al., 1993) all suggest that MOG functions as an adhesion molecule or cellular receptor. The L2/HNK-1 epitope found on MOG has also been identified on MAG and P0, both of which are myelin-specific proteins with adhesive properties (Burger et al., 1992). Unlike P0, however, transient expression of MOG in COS cells did not cause the cell clumping indicative of self-association (Hilton et al., 1995), implying that if MOG does have an adhesive function, it probably interacts with another CNS component apart from itself. It has been postulated that if MOG does have a significant role in cellular adhesion, this could involve MOG acting as the adhesive “glue” between neighboring myelinated fibers (Bernard et al., 1997 ; Burger et al., 1993), an event that takes place very late in the myelination process. Such a proposal is supported by the fact that in contrast to CNS myelin sheaths, PNS myelin sheaths, where MOG is not expressed, do not appear to be in contact with each other. This potential function of MOG is also in agreement with its relatively late expression, an observation consistent with the notion that MOG is associated with the completion and/or compaction of the myelin sheath. However, there is no direct evidence supporting this adhesive function for MOG, and a potential myelin-specific ligand for MOG has not been identified.

MOG as a regulator of microtubular stability

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Several experiments performed by Dyer and Matthieu (1994) have identified another possible function for MOG. They showed that the 8-18C5 anti-MOG antibody may mimic the putative ligand for MOG, as its addition to oligodendrocytes in culture causes the MOG/MOG antibody complex to redistribute over internal domains of MBP and the subsequent depolymerization of microtubules. As microtubules are stabilized by the cytoplasmic domains of MBP (Pirollet et al., 1992), the authors suggested that MBP may have an important role in this process. Our recent demonstration that the 8-18C5 antibody causes MBP degradation in purified myelin (Johns et al., 1995 ; Menon et al., 1997) provides a possible mechanism for this observation. Thus, we suggest that addition of 8-18C5 to oligodendrocytes causes the localized degradation of MBP, which in turn leads to microtubular depolymerization. Accordingly, one of the functions of MOG could be to regulate oligodendrocyte microtubule stability, which may become excessive as levels of MBP increase during myelination. Indeed, it is noteworthy that excessive stabilization of the microtubules in oligodendrocytes by taxol results in retraction of the normal myelin sheath (Benjamins and Nedelkoska, 1994), demonstrating that ongoing microtubule turnover is important for the myelination process. It is interesting that the CE1 antibody, which is directed to the myelin oligodendrocyte-specific protein, has the opposite effect to MOG and causes an increase in microtubule stability (Dyer and Matthieu, 1994). Therefore, it is possible that the interplay between signals generated by these proteins determines the dynamics of microtubule stabilization in oligodendrocytes.

Dyer (1993) also reported that antibodies to galactocerebroside (Gal-C) provoked depolymerization of microtubules in oligodendrocytes. Furthermore, we recently showed that incubation of purified myelin with Gal-C antibodies caused the phosphorylation and degradation of MBP in a manner analogous to some MOG-specific antibodies (Menon et al., 1997). Thus, it appears that MOG and Gal-C may share at least one function in common : regulation of microtubule stability through localized degradation of MBP. The mechanism by which two such diverse molecules, one being a lipid and the other a protein, could activate the same signaling pathway is not immediately apparent. However, the recent observation by Kroepfl et al. (1996) that the C-terminal tail of MOG is located within the cytoplasm provides one possible explanation. When MOG is expressed in human embryonic kidney cells, antibodies to the C-terminal peptide only recognized MOG following membrane permeabilization. In contrast, antiserum directed to peptides derived from the external Ig-like domain of MOG do not require membrane permeabilization for binding. This result implies that the C-terminal portion of the MOG is located within the cytoplasm and that the second hydrophobic domain is associated with the lipid bilayer rather than spanning it as first postulated (Fig. 3). Such an orientation would leave the cysteine residues at position 177 and 198 in juxtamembrane positions (Kroepfl et al., 1996), thus making them ideal targets for reversible palmitoylation (Casey, 1995) and providing a mechanism for further modulating the interaction of MOG with the cell membrane. Furthermore, we propose that the 24-carbon long-chain fatty acid (lignocerate) found in Gal-C may interact with the lipid-modified form of MOG, although the exact nature of this interaction is unknown (Fig. 3). Therefore, one function of Gal-C could be to modulate the interaction of MOG with the myelin membrane. Using antisera specific to Gal-C and immunoprecipitation, it should be possible to determine if such a linkage exists. This hypothesis would also explain how some antibodies to both MOG or Gal-C could activate the same signaling pathway. Antibodies to either molecule would have the potential to alter the putative intracellular interactions between MOG and various molecules associated with signal transduction. We are currently investigating the identity of those intracellular proteins and/or lipids associated with MOG, with the aim of further determining the function of MOG.

image

Figure 3. Proposed model for MOG membrane topology based on that of Kroepfl et al. (1996). In this model, the Ig-like domain and its associated N-linked carbohydrate moiety are extracellular, whereas the first hydrophobic domain appears to be a typical transmembrane sequence. In contrast, the second hydrophobic domain is probably associated with the membrane but not spanning it. The two cysteine residues at positions 177 and 198 appear to be ideal targets for palmitoylation. Given that ligand-mimicking antibodies to MOG and Gal-C both activate the same signal transduction pathway, we hypothesize that the fatty acid portion of Gal-C may interact with the lipid-modified form of MOG.

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MOG as an activator of complement

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

The localization of the MOG gene within the MHC (Pham-Dinh et al., 1993), its homology to the B-G antigens of the chicken MHC (Gardinier et al., 1992), its structural similarity to the B7 gene family (Linsley et al., 1994), and its ability to elicit strong immune responses (for review, see Bernard et al., 1997) have led to the speculation that MOG may have an immune function within the CNS. Furthermore, the recent preliminary report suggesting that MOG may be expressed on a subset of neutrophils also supports the idea of an immune function for MOG (Gardinier and Ballenthin, 1997). Finally, although the absence of MOG in the myelin of nonmammalian species can be interpreted in several ways, one possible explanation is that MOG does not have a direct role in the myelination process ; rather, it may mediate interactions between myelin and another component of the body such as the immune system. One immune function relatively unique to CNS myelin, but not PNS myelin, is its ability to activate directly the classical pathway of complement (Vanguri and Shin, 1986). Thus, CNS myelin must contain a protein capable of binding the C1q component of complement leading to the activation of complement. This observation is not restricted to purified myelin. Rat oligodendrocytes grown in vitro in the absence of cell-specific antibodies are lysed by homologous serum owing to the activation complement and its subsequent deposition on the cell surface (Scolding et al., 1989b ; Wren and Noble, 1989). The external location of MOG, its oligodendrocyte specificity, its absence from the PNS, and its possible immune involvement make this molecule an attractive candidate for this function. Consequently, we decided to test the possibility that MOG could bind the C1q component of complement. We were able to demonstrate that highly purified native MOG and the recombinant extracellular Ig-like domain of MOG both bind C1q in a dose-dependent and saturating manner (Johns and Bernard, 1997). Purified MOG also inhibited the antibody-dependent lysis of red blood cells by complement, suggesting that the MOG not only binds C1q, but also may be the protein in myelin responsible for complement activation (Johns and Bernard, 1997). The direct interaction between a myelin-specific protein and C1q has significant implications for CNS inflammation and could be particularly important in demyelinating diseases such as multiple sclerosis. Furthermore, if the presence of soluble MOG is confirmed at the protein level, it may function as a CNS-specific inhibitor of complement by binding to C1q. Our laboratory is currently conducting experiments to determine if MOG alone is able to activate complement and if the binding of C1q to myelin is able to initiate the same biochemical events in oligodendrocytes as the 8-18C5 antibody. It is possible, however, that another MOG ligand may be responsible for this effect and that the C1q interaction may only be important during CNS inflammation.

POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

Polymorphisms or mutations in the MOG gene may contribute to the development and/or progression of multiple sclerosis by various mechanisms, including increased and/or inappropriate expression of MOG leading to the breaking of immune tolerance, amino acid substitutions that produce immune cross-reactivity between MOG and environmental factors, and a loss of function that causes myelin to become more susceptible to autoimmune attack. With regard to the functional considerations of MOG, the interaction between MOG and C1q is potentially interesting. The complete absence of C1q almost always results in the autoimmune condition known as systemic lupus erythematosus. The form of systemic lupus erythematosus experienced by this group of patients is relatively homogeneous and includes a severe photosensitive skin rash caused by an autoimmune response to cutaneous autoantigens (Korb and Ahearn, 1997). Like myelin, apoptotic keratinocytes have the ability to bind specifically C1q in the absence of antibody (Korb and Ahearn, 1997), leading to the suggestion that the lack of C1q may prevent the efficient removal of these cells. As the surface blebs of these apoptotic keratinocytes are a concentrated source of several autoantigens identified in these patients, the prolonged presence of these apoptotic cells may help break self-tolerance. Analogous to apoptotic keratinocytes, the activation of complement by myelin and oligodendrocytes may be important in the opsonization and subsequent removal of myelin debris (Johns and Bernard, 1997). If this process is impaired, then damaged myelin may remain in the CNS for extended periods, acting as a reservoir for myelin-specific autoantigens and possibly resulting in a breakdown of self-tolerance. Mutations in the MOG gene effecting the binding of C1q to myelin is one avenue by which this could occur. The fact that C1q-deficient patients do not routinely develop multiple sclerosis indicates that this hypothesis cannot directly explain the development of this disease ; rather, it may be a contributing component in a subset of patients. Other necessary factors may include HLA background, the presence of other unknown susceptibility genes, or exposure to various environmental agents such as viruses.

The possibility that alterations to the MOG gene could be associated with multiple sclerosis has been examined by several researchers, albeit in a relatively superficial fashion. Roth et al. (1995) recently identified three highly polymorphic microsatellites, consisting of variable-length GA/GT dinucleotide repeats, within the region of the MOG gene. Analysis of these microsatellites by this group showed that their distribution was not significantly different in controls and multiple sclerosis patients. In contrast, another study showed that the presence of one of these alleles was significantly decreased in multiple sclerosis patients compared with controls and that this effect was independent of any HLA influence (Barcellos et al., 1997). However, this observation needs to be confirmed in a larger and different population of multiple sclerosis patients. A preliminary study from our laboratory has identified a Taq-1 restriction enzyme fragment length polymorphism associated with multiple sclerosis patients (Hilton et al., 1995). This polymorphism was not exclusive to multiple sclerosis as it was also found in a small number of control samples. Once again, this linkage needs to be confirmed, and its exact location within the MOG gene must be identified. Finally, a new polymorphism in the transmembrane region of MOG has been described (Rodriguez et al., 1997). This change involves the substitution of isoleucine for valine at amino acid position 145. An extensive comparison between controls and multiple sclerosis patients, however, did not show any significant difference in association between these two polymorphisms. Clearly, a more detailed analysis of the MOG gene is required to determine if any of these alterations are significant in the development of multiple sclerosis. Furthermore, the possibility of independent mutations within the MOG gene has not been examined. To this end, we are currently sequencing the extracellular domain of MOG from a large number of controls and multiple sclerosis patients to determine the presence of any such mutations.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

We now have substantial knowledge regarding the molecular and biochemical aspects of MOG. However, this information has failed to provide us with an obvious function for this quantitatively minor CNS component in the myelination process. Some of our data suggest that MOG has a significant role in the interaction between myelin and the immune system, but it is not known if this precludes a second function in myelination. Ultimately, the targeted disruption of the MOG gene in mice may help to elucidate further the biological function of MOG, although this approach has not always been completely successful when applied to other myelin proteins (Li et al., 1994). Researchers will continue to investigate how immune responses to MOG can promote autoimmune-mediated demyelination, but it is conceivable that the functional attributes of MOG may also contribute to the initiation and/or progression of these diseases. In particular, possible polymorphisms and mutations within the MOG gene need to be further investigated to determine if they have a role in diseases such as multiple sclerosis. Thus, determining the biological role of MOG in health and disease should remain an important and challenging goal.

Acknowledgements

  1. Top of page
  2. Abstract
  3. BIOCHEMISTRY OF MOG
  4. MOLECULAR BIOLOGY OF MOG
  5. Cloning of MOG cDNA
  6. Marsupial MOG cDNA
  7. Genomic organization of MOG
  8. MOG splice variants
  9. MOG promoter region
  10. Chromosomal location of MOG
  11. POSSIBLE FUNCTIONS OF MOG
  12. MOG as an adhesion molecule
  13. MOG as a regulator of microtubular stability
  14. MOG as an activator of complement
  15. POSSIBLE RELATIONSHIP BETWEEN THE MOLECULAR ASPECTS OF MOG AND MULTIPLE SCLEROSIS
  16. CONCLUSIONS
  17. Acknowledgements

We thank Sharon Harris for her expert secretarial assistance, Roslyn Clark for the sequence of marsupial MOG, David Walsh for the artwork, and Drs. Ora Bernard and Anthony Slavin for their critical review of the manuscript. Aspects of this work were funded by the National Health and Medical Research Council of Australia and the Multiple Sclerosis Society of Australia.

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