Myelin-Associated Glycoprotein in Myelin and Expressed by Schwann Cells Inhibits Axonal Regeneration and Branching

Shen, Ying Jing; DeBellard, Maria Elena; Salzer, James L.; Roder, John; Filbin, Marie T.

doi:10.1006/mcne.1998.0700

Cited by 126 publications

(86 citation statements)

References 44 publications

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“…3A, columns 1 and 2). This finding is consistent with the myelin inhibition reported for cerebellar granule and dorsal root ganglion neurons (7,25,26). Removal of ephrin-B3 from the myelin substrate (by using ephrin-B3 knockout myelin) significantly relieved this inhibition (Fig.…”

Section: Resultssupporting

confidence: 90%

“…Removal of ephrin-B3 from the myelin substrate (by using ephrin-B3 knockout myelin) significantly relieved this inhibition (Fig. 3A, columns 2 and 3), comparable with results reported for neurons cultured on myelin from Nogo A͞B or MAG knockout mutant mice (25,26). Western analysis of our myelin preparations confirmed that this relief of inhibition was not due to changes in the levels of Nogo, MAG, or OMgp in the myelin of knockout versus WT mice (data not shown).…”

Section: Resultssupporting

confidence: 87%

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Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

Benson

Romero

Lush

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

278

191

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The inability of CNS axons to regenerate after traumatic spinal cord injury is due, in part, to the inhibitory effects of myelin. The three major previously identified constituents of this activity (Nogo, myelin-associated glycoprotein, and oligodendrocyte myelin glycoprotein) were isolated based on their potent inhibition of axon outgrowth in vitro. All three myelin components transduce their inhibitory signals through the same Nogo receptor͞p75 neurotrophin receptor͞LINGO-1 (NgR1͞p75͞LINGO-1) complex. In this study, we considered that molecules known to act as repellants in vertebrate embryonic axonal pathfinding may also inhibit regeneration. In mice, ephrin-B3 functions during development as a midline repellant for axons of the corticospinal tract. We therefore investigated whether this repellant was expressed in the adult spinal cord and retained inhibitory activity. We demonstrate that ephrin-B3 is expressed in postnatal myelinating oligodendrocytes and, by using primary CNS neurons, show that ephrin-B3 accounts for an inhibitory activity equivalent to that of the other three myelin-based inhibitors, acting through p75, combined. Our data describe a known vertebrate axon guidance molecule as a myelinbased inhibitor of neurite outgrowth.spinal cord injury ͉ regeneration ͉ axon ͉ Eph receptor T he corticospinal tract (CST) is the major spinal axon bundle responsible for fine locomotor control. Damage to this tract contributes to the permanent loss of motor control that is the most visible hallmark of spinal cord injury (SCI). These, and other axons of the CNS damaged in SCI, do not regenerate, in part, because of the nonpermissive environment of myelin in the mature CNS (1). Constituents of this repressive activity in myelin include Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte myelin glycoprotein (OMgp) (reviewed in ref.2). The recently identified Nogo receptor (NgR1) is a glycosylphosphatidylinositol-linked molecule that binds the 66-aa extracellular loop of Nogo (Nogo-66) and transduces its inhibitory activity when expressed in neurons (3). Surprisingly, MAG and OMgp also bind the NgR1 (4-6) in a complex with the p75 neurotrophin receptor and the newly characterized leucine rich repeat transmembrane protein LINGO-1. p75 and LINGO-1 are requisite signaling components for inhibition by Nogo-66, MAG, and OMgp as p75 Ϫ/Ϫ cerebellar granule neurons (CGNs) or dorsal root ganglion (DRG) neurons exhibit reduced sensitivity to these three inhibitors and to inhibition by CNS myelin (7), and NgR1͞p75 complexes confer sensitivity to these inhibitors only in the presence of LINGO-1 (8).Although it is thought that Nogo, MAG, and OMgp may act in the uninjured CNS to control aberrant sprouting and stabilize mature connections (9), their normal and developmental roles remain a mystery. Axon repellants such as semaphorins, slits, and ephrins play critical roles in tract formation during embryonic development (10). We previously proposed that such molecules may function as inhibitors of regeneration in the...

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Section: Resultssupporting

confidence: 90%

Section: Resultssupporting

confidence: 87%

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

Benson

Romero

Lush

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

278

191

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“…Alteration in PMP-22 represent 70% of myelinopathy (Young et al, 2003), in demyelinating human peripheral fibers, we observed axonal sprouting consequently with the lack of inhibitory effect of myelin and normal Schwann cell (Shen et al, 1998;De Bellard et al, 1996). This axonal growing is in close relation with structural and functional changes, as observed among myelin disassembly, axonal sprouting.…”

Section: Schwann Cells' Ribosomes Are Involved In Axonal Sprouting Ofmentioning

confidence: 51%

The Schwann Cell-Axon Link in Normal Condition or Neuro-Degenerative Diseases: An Immunocytochemical Approach

Kun¹,

Rosso²,

Canclini³

et al. 2012

Applications of Immunocytochemistry

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“…Myelin was isolated from the lumbar part of the spinal cord of sedentary animals or animals that had exercised for 7 days, by sucrose density gradient centrifugation as previously reported (Carson et al, 1993;Norton and Poduslo, 1973;Shen et al, 1998). Briefly, after sacrifice, the rat spinal cord was rapidly removed and homogenized in 0.32 M sucrose using a Teflon/Glass homogenizer, then, layered over an equal volume of 0.85 M sucrose.…”

Section: Preparation Of Myelinmentioning

confidence: 99%

Exercise decreases myelin‐associated glycoprotein expression in the spinal cord and positively modulates neuronal growth

Ghiani

Ying

Vellis

et al. 2007

Glia

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To successfully grow, neurons need to overcome the effects of hostile environments, such as the inhibitory action of myelin. We have evaluated the potential of exercise to overcome the intrinsic limitation of the central nervous system for axonal growth. In line with the demonstrated ability of exercise to increase the regenerative potential of neurons, here we show that exercise reduces the inhibitory capacity of myelin. Cortical neurons grown on myelin from exercised rats showed a more pronounced neurite extension compared with neurons grown on poly-D-lysine, or on myelin extracted from sedentary animals. The activity of cyclin-dependent kinase 5, a kinase involved in neurite outgrowth, was found to be increased in cortical neurons grown on exercise-myelin and in the lumbar spinal cord enlargement of exercised animals. Exercise significantly decreased the levels of myelinassociated glycoprotein (MAG), a potent axonal growth inhibitor, suggesting that downregulation of MAG is part of the mechanism through which exercise reduces growth inhibition. It is known that exercise elevates brain-derived neurotrophic factor (BDNF) spinal cord levels and that BDNF acts to overcome the inhibitory effects of myelin. Accordingly, we blocked the action of BDNF during exercise, which suppressed the exercise-related MAG decrease. Protein kinase A (PKA) has been related to the ability of BDNF to overcome growth inhibition; in agreement, we found that exercise increased PKA levels and this effect was reverted by blocking BDNF. Overall, these results show that exercise promotes a permissive cellular environment for axonal growth in the adult spinal cord requiring BDNF action.

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Myelin-Associated Glycoprotein in Myelin and Expressed by Schwann Cells Inhibits Axonal Regeneration and Branching

Cited by 126 publications

References 44 publications

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth

The Schwann Cell-Axon Link in Normal Condition or Neuro-Degenerative Diseases: An Immunocytochemical Approach

Exercise decreases myelin‐associated glycoprotein expression in the spinal cord and positively modulates neuronal growth

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