ORIGINAL PAPER

A Hypothesis About the Relationship of Myelin-AssociatedGlycoproteins Function in Myelinated Axons to its Capacityto Inhibit Neurite Outgrowth

Richard H. Quarles

Accepted: 12 March 2008 / Published online: 12 April 2008

Springer Science+Business Media, LLC 2008

Abstract The myelin-associated glycoprotein (MAG) is

selectively localized in periaxonal Schwann cell and oli-

godendroglial membranes of myelin sheaths suggesting

that it functions in gliaaxon interactions in the PNS and

CNS, and this is supported by much experimental evi-

dence. In addition, MAG is now well known as one of

several white matter inhibitors of neurite outgrowth in

vitro and axonal regeneration in vivo, and this latter area of

research has provided a substantial amount of information

about neuronal receptors or receptor complexes for MAG.

This article makes the hypothesis that the capacity of MAG

to inhibit outgrowth of immature developing or regener-

ating neurites is an aberration of its normal physiological

function to promote the maturation, maintenance, and

survival of myelinated axons. The overview summarizes

the literature on the function of MAG in PNS and CNS

myelin sheaths and its role as an inhibitor of neurite out-

growth to put this hypothesis into perspective. Additional

research is needed to determine if receptors and signaling

systems similar to those responsible for MAG inhibition of

neurite outgrowth also promote the maturation, mainte-

nance, and survival of myelinated axons as hypothesized

here, or if substantially different MAG-mediated signaling

mechanisms are operative at the gliaaxon junction.

Keywords Axonglia interactions Gangliosides Myelin-associated glycoprotein Myelinated axons Neurite outgrowth inhibition Nogo receptor Sialic acid

Abbreviations

MAG Myelin-associated glycoprotein

MS Multiple sclerosis

NgR Nogo receptor

p75NtR p75 Neurotrophin receptor

OMgp Oligodendrocyte-Myelin glycoprotein

2,3- or 2,6-SA a2,3- or a2,6-linked sialic acidsiglec Sialic acid-binding immunoglobulin-like

lectin

Introduction

The selective localization of the myelin-associated glyco-

protein (MAG) in periaxonal Schwann cell and

oligodendroglial membranes of myelin sheaths suggests

that it functions in gliaaxon interactions in the PNS and

CNS. Furthermore, there is a substantial body of published

experimental data supporting this concept (reviewed in

[1]). In addition, MAG is now well known as one of several

white matter inhibitors of neurite outgrowth in vitro and

axonal regeneration in vivo (reviewed in [2, 3]), and this

latter area of research has provided a substantial amount of

information about neuronal receptors or receptor com-

plexes for MAG. However, It is not yet clear how the

information obtained from MAG inhibition of neurite

outgrowth relates to its function in the periaxonal glial

membranes of myelinated axons. The principal objective of

this article is to propose the hypothesis that the capacity of

MAG to inhibit outgrowth of immature developing or

Special issue article in honor of Dr. George DeVries.

R. H. Quarles (&)National Institute of Neurological Disorders and Stroke,

NIH, 5625 Fishers Lane, Rm. 4S-30, MSC 9407,

Bethesda, MD 20892, USA

e-mail: quarlesr@ninds.nih.gov

123

Neurochem Res (2009) 34:7986

DOI 10.1007/s11064-008-9668-y

regenerating neurites is an aberration of its normal physi-

ological function to promote the maturation, maintenance,

and survival of myelinated axons.

The Role of MAG in GliaAxon Interactions

Within Myelinated Axons

The periaxonal localization of MAG, its five immuno-

globulin-like domains, and the abnormalities in MAG-

deficient mice all implicate MAG in gliaaxon interactions

related to the formation and maintenance of myelin

sheaths. Furthermore, it appears that MAG may participate

in signaling in both directions between axons and glia. It

had long been thought that MAG was likely to be a glial

receptor for an axonal signal that promotes myelination,

and some findings do support such a role, especially in the

CNS [1]. MAG expression begins very early in the process

of myelination [48], so it could function in the initial

interactions of oligodendroglial processes with axons and

in the molecular mechanisms by which oligodendroglial

and Schwann cell membranes wrap around axons to form

myelin. However, it also appears that MAG is a ligand that

binds to a receptor on the axonal surface of myelinated

axons and thereby affects axonal properties. MAG

expression continues at a relatively high level in mature

animals consistent with important functions in the main-

tenance of myelin and myelinated axons. It is the signaling

from glial cells to the axons that will be emphasized here,

because that is the signaling that is most likely to be related

to MAGs capacity to inhibit neurite outgrowth.

Research on two lines of MAG knockout mice [9, 10]

has played a key role in forming our concepts of MAG

function. Representative electron micrographs illustrating

some of the key points described here are included in two

review articles that emphasize MAG-null mice [5, 11].

Behavioral studies on MAG-null mice have produced

variable results, but as a whole they demonstrate functional

and locomotor neurological deficits [9, 10, 12, 13]. These

mice exhibit subtle structural abnormalities in the periax-

onal region of myelin sheaths, consistent with MAGs

periaxonal localization. Although they form compact

myelin relatively normally, myelination in the CNS is

significantly delayed. Other CNS anomalies include aber-

rant or redundant myelin loops, supernumerary myelin

sheaths, and mild disorganization of the gliaaxon junc-

tions in the paranodal regions. However, the most

pronounced abnormality as the MAG-null mice age was

first reported in the PNS and consists of degeneration of

myelinated axons in sciatic nerves [14, 15]. The amount of

compact myelin in the nerves appears normal. Rather, the

pathology is associated with decreased axonal caliber,

increased neurofilament density, reduced expression, and

phosphorylation of neurofilaments and eventual axonal

degeneration. Early electrophysiological studies on rela-

tively young MAG-null mice (less than 5 months) did not

reveal abnormalities [10, 12]. However, evaluation of sci-

atic nerves in 1-year old MAG-null mice demonstrated a

mild, but statistically significant, reduction of conduction

velocity and small decreases in compound muscle action

potential amplitudes that did not reach statistical signifi-

cance [15]. Overall, these findings, taken in the context of

the ultrastructural and biochemical studies on these

mutants, are consistent with an axonopathy of the PNS that

progresses with age in the absence of MAG, rather than a

demyelinating neuropathy.

The capacity of myelination to increase the caliber of

axons in internodes via a mechanism involving expression

and phosphorylation of neurofilaments has been known for

many years (reviewed in [16]). The findings in MAG-null

mice suggest that MAG is a ligand at the inside of myelin

sheaths that binds to an axonal receptor to mediate this

effect. However, the structural disruption of the periaxonal

region in myelinated axons of MAG-null mice raises the

possibility that a general loosening of the gliaaxon junc-

tion in vivo could interfere with other signaling systems in

which MAG does not participate directly. That uncertainty

was circumvented by in vitro models in which neurons

were co-cultured with MAG-transfected COS cells or

treated with a soluble MAG-Fc chimera [17]. The presence

of MAG resulted in increased expression and phosphory-

lation of neurofilament subunits and microtubule

associated proteins together with up-regulation of cyclin

dependent kinase-5 and extracellular signal regulated

kinases 1 & 2, both of which phosphorylate axonal cyto-

skeletal components and are decreased in MAG-null mice.

These in vitro results substantially reinforce the concept

that MAG itself is a component of a signaling system that

affects the axonal cytoskeleton

Early studies on the CNS of aging MAG-null mice

indicated that myelinated axons appeared normal [12, 18],

but more recent reports demonstrate axonal pathology in

the CNS as the mice age. In one report [19], the axonal

injury consisted of focal swellings and spheroids, whereas

in a different report [13] quantitatively and qualitatively

similar decreases in axonal diameter and neurofilament

spacing as well as axonal degeneration were reported for

both the CNS and PNS. The mice in the latter study had

been backcrossed from the mixed background on which

they were generated to the C57BL/6 background, and it

was suggested that the importance of MAG for the main-

tenance of CNS axons may depend on the overall genetic

background. Other possibilities are that the two indepen-

dent lines of MAG knockout mice [9, 10] are different in

some respects or that there are regional differences in the

extent of axonal degeneration in the CNS. Further

80 Neurochem Res (2009) 34:7986

123

investigations are needed before a full understanding of the

relative importance of MAG for the maintenance and

structural integrity of CNS and PNS myelinated axons is

achieved. Nevertheless, it is clear that MAG participates in

a signaling system within the periaxonal region of myelin

sheaths that is necessary for the maintenance and survival

of some axons.

Information About Biochemical Mechanisms of MAG

Function Revealed by its Inhibition of Neurite

Outgrowth

In recent years, a substantial amount of information has

been obtained about a neuronal receptor complex for MAG

from investigation of several white matter inhibitors of

neurite outgrowth in vitro and neuronal regeneration

in vivo (Fig. 1). The inhibitors include MAG, oligoden-

drocyte-myelin glycoprotein (OMgp) and Nogo, all three

of which appear to act via the Nogo receptor (NgR) despite

the fact that they have little structural similarity. MAG can

inhibit or promote neurite outgrowth depending on the

developmental status of the neuron and other factors, but

most emphasis has been placed on its inhibitory properties

because of the potential relevance to regeneration follow-

ing neural injury. Recent reviews of this active area of

research are available [2, 3], and it will not be considered

in detail here. Nevertheless, the information obtained about

a neuronal receptor for MAG from this research may be

relevant to MAGs physiological function in the formation

and maintenance of myelinated axons. However, it is not

obvious how the capacity of MAG to inhibit outgrowth of

immature or regenerating neurites would relate to its nor-

mal physiological function. MAG is not present early in

development during the most active phase of neurite out-

growth. Later in development it is sequestered at the inside

of myelin sheaths, where it would not be accessible to

interact with growing neurites. Therefore, the hypothesis of

Raisman [20] that the physiological role of myelin-related

inhibitors is actually to facilitate rapid longitudinal axonal

growth along pre-existing myelinated tracts via a repulsive

guidance-contact mechanism may apply to Nogo and

OMgp, but probably not to MAG. A possible functional

role for MAG and the other inhibitors is that they prevent

the sprouting of neuronal processes that could interfere

with the spiraling of glial membranes around axons to form

myelin early in development. Huang et al. [21] reported

that OMgp in the nodal axoglial apparatus is particularly

important in preventing collateral axonal sprouting at

nodes of Ranvier, although some MAG was detected in

these structures and also could play a role. Nevertheless,

expression of MAG continues at high levels in adults, and

the observations on MAG-null mice demonstrate that it has

essential functions in the maintenance of mature myelin-

ated axons. Actually, the capacity of MAG to inhibit

outgrowth of immature neurites is consistent with a MAG-

mediated signaling mechanism that could promote the

maturation of axons during the formation of adult mye-

linated axons. Thus, a physiologically important signal

promoting the maturation and stability of myelinated axons

could be interpreted inappropriately by a plastic developing

neurite in vitro or a regenerating neurite in vivo, thereby

inhibiting its growth. Whether or not the inhibition of

neurite outgrowth by MAG, which is well established

in vitro, is also a significant factor in preventing regener-

ation in vivo following neural injury is not as clear. MAG

may be released from its sequestered periaxonal localiza-

tion during degeneration following tissue injury so it could

be accessible to regenerating neurons. Indeed in the CNS, a

proteolytic derivative of MAG [22], consisting of its sol-

uble extracellular domain [23], is released in some

neurological disorders [24] and has been shown to inhibit

neurite outgrowth in vitro [25].

In addition to the NgR, some gangliosides have also

been shown to be MAG receptors involved in the inhibition

of neurite outgrowth [26, 27] (Fig. 1). MAG is in the

siglec (sialic acid-binding immunolgobulin-like lectin)

subgroup of the Ig superfamily [11, 28, 29], whose mem-

bers exhibit high homology in the first two amino terminal

Ig-like domains and bind to sialic acid-containing oligo-

saccharides [30]. In the siglec nomenclature, MAG is

siglec-4a, and siglec-4b is Schwann cell myelin protein in

birds that could be the avian ortholog of MAG. The linkage

of sialic acid to the underlying sugar is a very important

determinant of siglec binding, and MAG shows high

specificity for a2,3-linked sialic acid (2,3-SA) in compar-ison to a2,6-linked sialic acid (2,6-SA). It binds well tooligosaccharides with 2,3-SA on a core structure of Galb1-3GalNAc found in some gangliosides, such as the major

GD1a and GT1b brain gangliosides as well as some minor

ones [28, 31], and in O-linked oligosaccharides on glyco-

proteins. However, MAG also binds to N-linked

oligosaccharides with 2,3-SA on glycoproteins [32, 33].

The fact that MAG binds to oligosaccharides on both

glycoproteins and gangliosides indicates that there are

likely to be many binding-partners on neuronal mem-

branes. Furthermore, a potentially important general

consideration with regard to MAGs sialic-acid binding

properties in signal transduction is the substantial differ-

ence in the predominant sialic acid linkages on

glycoproteins of the CNS and PNS. Whereas most of the

sialic acid on glycoproteins in the CNS is 2,3-linked, most

is 2,6-linked in the PNS [34]. Another difference is that the

PNS also contains lower levels of gangliosides, especially

those in the ganglio-series including GD1a and GT1b [35].

Binding and signal transduction to adjacent cells by MAG

Neurochem Res (2009) 34:7986 81

123

and other siglecs may be regulated by overall levels of both

cis and trans sialic acid [30, 36]. Thus if binding to any

glycoconjugate containing 2,3-SA on the adjacent cell is

sufficient for a MAG function, that would occur more

readily in the CNS. However, if interaction must be with a

specific binding partner, this could occur more readily in

the PNS because the high level of 2,3-SA in the CNS could

mask the correct binding partner. The latter circumstance

might explain the higher levels of MAG in the CNS than

the PNS, which would be needed to overcome the greater

degree of masking.

There have been two sets of findings about the receptor

that transmits the MAG-mediated signal that inhibits neu-

rite outgrowth that initially seemed to differ with regard to

the relevance of the sialic acid-binding capacity of MAG

(Fig. 1) (reviewed in [2, 3]). Early reports on the inhibition

indicated that it was sialic acid-dependent [37], although

this might only reflect a MAG docking mechanism and a

Inhibition of neurite outgrowth ? Maturation, maintenance and survival of myelinated axons

"raft"

Sialic acid-dependent

Glialmembrane

Neuronalmembrane

MAGMAG

Combined model

glycoprotein ganglioside ganglioside / p75NtR NgR1 (or NgR2) / p75NtR (or TROY) / LINGO-1Receptors:

Glialmembrane

Neuronalmembrane

Nogo receptor complex

OMgpOMgp

NogoNogo MAGMAG

Fig. 1 Neuronal receptor complexes for MAG and the role of sialicacidBinding of MAG (yellow) to a component (green) on the

axolemma is likely to be sialic acid-dependent because MAG is a

lectin in the siglec family. Some published results support this (see

text), and three possibilities are schematically represented at the upper

left. The simplest would be MAG directly binding to a sialyloligo-

saccharide on a glycoprotein or ganglioside (both green), and one

report described a somewhat more complex situation in which a

ganglioside was an intermediary for the interaction of MAG with the

p75NtR. However, the initial reports that MAG was one of several

ligands for the NgR (also green) (upper right) indicated that MAG

binding was sialic acid-independent and that p75NtR interacted

directly with NgR. This receptor complex is located in lipid rafts

(pink). Other ligands for this receptor are Nogo itself (brown) and

OMgp (dark blue). In addition, TROY can substitute for p75NtR in

the receptor complex, and LINGO-1 (red) is another component of the

complex that interacts with both NgR and p75NtR, but does not bind

any of the ligands. A more recent report modified the situation with

regard to sialic acid dependence with the demonstration that both

NgR1 and its NgR2 isoform expressed in neurons bind MAG in a

sialic acid-dependent manner. Furthermore, NgR2 binds MAG more

strongly than NgR1, and does not bind Nogo or OMgp. See text for

original references about the various components in the NgR

complexes. A possible combined model incorporating many compo-

nents of both schemes is illustrated at the bottom of the figure. Here

components of the receptor complex are localized together in a lipid

raft by a variety of different interactions with each other and with

MAG, some of which are sialic acid-dependent and others sialic acid-

independent. The sialic acid-dependent interactions could include

recruitment of MAG and p75NtR to the complex by interaction with

gangliosides and the strong binding of MAG to NgR2. It remains to

be established if a receptor complex such as this, which may function

in the inhibition of neurite outgrowth (arrow to the left), is also

involved in gliaaxon interactions within the periaxonal space of

myelinated axons that promotes their maturation, maintenance and

survival (arrow to the right). Furthermore, it should be noted that of

the three ligands shown for the NgR, only MAG is selectively

localized in the periaxonal glial membrane, whereas Nogo and OMgp

are much more widely distributed. Also this figure depicts all three as

being localized in the adjacent glial membrane, whereas they are

likely to be in degrading membrane fragments or released proteins

when they act to inhibit neurite outgrowth following neural injury.

Modified from Fig. 3 in Ref. [1] with permission

82 Neurochem Res (2009) 34:7986

123

separate polypeptide-binding site is needed for outgrowth

inhibition [38]. Indeed, this polypeptide-binding site was

recently identified to be in Ig-domain 5 of MAG that is

closest to the glial membrane and far removed from the

sialic acid-binding site in terminal Ig-domain 1 [39].

However, the first reports of MAG interaction with the

NgR expressed in non-neural cells indicated that the

binding was sialic acid-independent [40, 41]. However, a

more recent report demonstrated sialic acid-dependent

binding of MAG both to NgR1 and its NgR2 homologue

expressed in neurons [42]. NgR2 bound MAG with higher

affinity than NgR1 and does not bind Nogo or OMgp,

raising the interesting possibility that NgR2 could be the

MAG receptor most relevant to its function in myelinated

axons. As mentioned above, other reports indicated that

gangliosides containing terminal 2,3-SA are functional

binding partners for MAG inhibition of neurite outgrowth

[26, 27]. Also, the p75 neurotrophin receptor (p75NtR) was

implicated as a signal transducing partner in the receptor

complex for MAG that was needed because neither the

phosphatidylinositol-linked NgR nor gangliosides span

the membrane to interact with signaling molecules on the

cytoplasmic side. Some reports demonstrated a direct

interaction between the p75NtR and the NgR [43, 44], but

one implicated an interaction of GT1b ganglioside with the

p75NtR, suggesting a role for sialic acid-binding in

bringing MAG and p75NtR together in the receptor com-

plex [45] (Fig. 1). Recent reports have identified LINGO-1

as another component of the complex and demonstrated

that Troy/TAJ can serve as an alternative co-receptor with

NgR in place of p75NtR (Fig. 1) (see [2, 3] for review).

The MAG receptor complex is present in lipid rafts [42, 46,

47], in which both gangliosides and phosphtidylinositol-

linked proteins are characteristic components. The NgR

and gangliosides may be part of independent receptor

systems for MAG, which could function in the same or

different types of neurons. Indeed, there are recent reports

showing that there are differences between types of neu-

rons with regard to the importance of sialic acid,

gangliosides, and NgRs for MAG inhibition of outgrowth

[48, 49]. However, it also seems possible that the variable

results with regard to sialic acid dependence could be

explained by the complex properties of raft-localized

receptor complexes with a variety of interactions between

the different components, as well as variable techniques

that were used by different investigators. A model com-

bining many aspects of the various reports about the sialic

acid-dependence or independence of signaling is shown at

the bottom of Fig. 1. The report that sialidase treatment

enhances spinal axon outgrowth in a model of traumatic

injury to rat nerve roots suggests that sialic acid-dependent

MAG signaling could be involved in outgrowth inhibition

in vivo [50].

The findings summarized above indicate that the

molecular mechanisms mediating the effects of MAG and

other white matter inhibitors on neuronal properties are

complex. However, taken as a whole, the results clearly

demonstrate that there is one or more receptor complexes

on the surface of developing or regenerating neurites that

transmit signals induced by MAG that cause inhibition of

neurite outgrowth. Also, much has been learned about the

intracellular signaling pathways that are affected by MAG

and the other white matter inhibitors and how they are

regulated [2, 3]. The signaling within neurons involves

activation of Rho and Rho kinase, activation of protein

kinase C, influx of calcium and eventual changes in the

actin and microtubular cytoskeleton that cause growth cone

collapse. More recent findings have implicated intramo-

lecular proteolysis of the p75 NtR by a- and b-secretases,downstream activation of the epidermal growth factor

receptor and inhibition of microtubule assembly via the

collapsing response mediator protein-2 [51]. With regard to

the normal physiological role of MAG, an important out-

standing question is whether or not similar neuronal

receptor complexes and intracellular signaling pathways

mediate the effects of MAG within myelinated axons that

are needed for their maturation, maintenance, and survival

(Fig. 1).

Localization of MAG Receptors

In order, for the potential MAG receptor complexes dis-

cussed above in the context of neurite outgrowth inhibition

to function in the physiological signaling affecting axonal

properties of myelinated axons in vivo, they must be

localized in the axolemma of myelinated axons. Ganglio-

sides are wide spread in neuronal membranes. Ganglioside

analysis of rat axolemma isolated from myelinated axons

of rat brain demonstrated the presence of all the major

brain gangliosides, including GD1a and GT1b that are

binding partners for MAG [52]. GT1b was also suggested

to be in the axolemma of myelinated axons in peripheral

nerve based on histochemical staining with tetanus toxin

fragment C [53].

Similarly to gangliosides, NgR1 and NgR2 are also

widely distributed in neurons of the postnatal brain,

although their distributions are somewhat different [42].

Immunohistochemistry showed that they are present

throughout the axons in internodes of myelinated fibers, but

not selectively concentrated in the axolemma [42, 54].

Recently, we used biochemical subfractionation procedures

to investigate whether components of the NgR receptor

complex are present in axolemma of rat brain myelinated

axons (R. Quarles, A. Sedlock, and R. Giger, unpublished

results). A modification of the procedure of DeVries et al.

Neurochem Res (2009) 34:7986 83

123

[55] for isolating axolemma enriched fractions (AEF) was

employed, and the fractions were analyzed by western

blotting. Both NgR1 and NgR2 as well as LINGO-1 were

in the AEF, suggesting that a NgR complex could partic-

ipate in MAG signaling within the periaxonal compartment

of myelinated axons. However, we were unable to detect

the p75NtR or TROY in the axolemma fraction, suggesting

than another transmembrane signal transducing component

could be involved. Alternative signal transducing agents

for NgRs have also been suggested by studies of MAG

inhibition of neurite outgrowth in different types of neu-

rons [48]. In addition, we attempted to demonstrate an

interaction between the endogenous MAG and NgR mol-

ecules by co-immunoprecipiation experiments using both

anti-MAG and anti-NgR antibodies. For these experiments,

we modified the gradients for subfractionation so that the

membrane fractions used included both AEF and a heavy

myelin fraction enriched in MAG-containing periaxonal

oligodendroglial membranes. However, these co-immuno-

precipitation experiments did not provide convincing

evidence for a significant interaction of MAG and NgR

within these membranes from myelinated axons. In sum-

mary, these experiments demonstrated the presence of key

components of the NgR complex within the axolemma of

myelinated axons consistent with their involvement in

MAG-mediated signaling at this location, but attempts to

demonstrate an interaction of the NgR with MAG in these

fractions by co-immunoprecipitation experiments were

unsuccessful in our hands. Clearly, further research is

needed to determine if and in what form a NgR complex is

involved in transmitting MAG-mediated signals to mye-

linated axons.

Conclusions and Perspectives

It is clear from studies on MAG-null mice that this gly-

coprotein is essential for the maintenance of myelinated

axons in the PNS. However, its importance for a similar

function in the CNS remains to be clarified in view of

differing reports. Factors requiring further investigation

that may be related to these differences include possible

CNS regional differences in the MAG-requirement for

axonal stability and the effect of genetic background of the

mice. It is also well established that MAG-mediated sig-

naling affects the caliber of PNS myelinated axons by

increasing the expression of phosphorylated neurofila-

ments, but essentially nothing is known about why PNS

axons actually degenerate in the absence of this signaling.

Much has been learned in the context of inhibition of

outgrowth of immature neurites about the neuronal NgR

complex for MAG and other white matter ligands as well

as MAG binding to ganglioside receptors. In addition much

is known about the intracellular signaling pathways within

neurons that are affected by MAG in this context. The

specificity of the NgR2 isoform for MAG, and not Nogo or

OMgp, provides an intriguing suggestion that it could be an

important specific receptor for MAG with regard to the

effect of MAG-mediated signaling to myelinated axons.

The underlying hypothesis of this paper is that the capacity

of MAG to inhibit neurite outgrowth is a manifestation of a

physiological MAG-mediated signaling mechanism for

promoting maturation and stability of axons to optimize

their properties for rapid saltatory conduction in myelin-

ated fibers.

Further research to test this hypothesis will be partic-

ularly challenging because the signaling occurs within the

sequestered periaxonal space of myelinated axons, which

is not readily modeled by in vitro systems. The presence

of MAG-binding gangliosides and some components of

the NgR receptor complex in the axolemma of myelinated

axons is consistent with the hypothesis. Furthermore,

mice lacking GM2/GD2 synthase and not expressing

complex gangliosides have been shown to exhibit simi-

larities to MAG-null mice including axonal degeneration

in the PNS and CNS [56], suggesting that gangliosides

could be part of functional receptors for MAG in the

axolemma. Careful examination of axonal structure and

stability in transgenic mice lacking various components of

the NgR complex could also be informative. An inter-

esting possibility is that the amount of 2,3-SA on trans

and cis glycoconjugates at the axonglia junction regu-

lates MAG-mediated signaling as appears to be the case

for other siglecs [30, 36].

The MAG-mediated signaling mechanisms affecting the

stability of myelinated axons are of potential clinical sig-

nificance, because MAG is lost earlier than most other

myelin components in the progression of many multiple

sclerosis (MS) lesions (reviewed in detail in [1]). Its loss

could contribute to axonal degeneration that is important

for the irreversible neurological deficits in MS and other

disorders of myelin [57]. An important objective of future

MAG research will be to determine if signaling systems

similar to those responsible for MAG inhibition of neurite

outgrowth also promote the maturation, maintenance, and

survival of myelinated axons as hypothesized here, or if

substantially different MAG-mediated signaling mecha-

nisms are operative at the gliaaxon junction.

Acknowledgments This article is dedicated to George DeVries, along time colleague and good friend. The subject is very appropriate

because George followed the MAG story closely as it evolved over

the years. Preparation of this review and covered research from our

laboratory were supported by the Intramural Research Program of

NINDS, NIH.

84 Neurochem Res (2009) 34:7986

123

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A Hypothesis About the Relationship of Myelin-Associated Glycoproteins Function in Myelinated Axons to its Capacity to Inhibit Neurite OutgrowthAbstractIntroductionThe Role of MAG in Glia-Axon Interactions Within Myelinated AxonsInformation About Biochemical Mechanisms of MAG Function Revealed by its Inhibition of Neurite OutgrowthLocalization of MAG ReceptorsConclusions and PerspectivesAcknowledgmentsReferences

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