Myelin-Associated Glycoprotein Inhibits Axonal Regeneration from a Variety of Neurons via Interaction with a Sialoglycoprotein

DeBellard, Maria-Elena; Tang, Song; Mukhopadhyay, Gauranga; Shen, Ying-Jing; Filbin, Marie T.

doi:10.1006/mcne.1996.0007

Cited by 168 publications

(129 citation statements)

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“…This indicates that the signalling that is exerted by this receptor complex might be different for old and young neurons. Moreover, most young neurons are not merely unresponsive to Mag; rather, neurite outgrowth is actually promoted 17,21,95 . It remains to be shown whether the Ngr-p75 NTR receptor complex is used for this promoting effect.…”

Section: Insight From Systems That Regenerate In Vivomentioning

confidence: 99%

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

2003

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Section: Insight From Systems That Regenerate In Vivomentioning

confidence: 99%

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

2003

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“…Myelin outgrowth assays were adapted from the method of DeBellard et al (19). Purified myelin was prepared by sucrose gradient centrifugation (20), and 3 g per well was used to coat poly(DL)-ornithine-coated glass eight-well chamber slides (LabTek II; Nunc) in a vacuum dessicator.…”

Section: Methodsmentioning

confidence: 99%

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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“…The transmembrane myelin proteins NogoA and MAG and the glycosylphosphatidylinositol (GPI)-anchored myelin protein OMgp are postulated to act by binding to a GPI-anchored family of receptors on axons, the Nogo receptors (NgRs) (14)(15)(16). MAG is also a member of the Siglec family of sialic acid-binding lectins (17) and has been proposed to inhibit axon regeneration by binding to axonal sialoglycoconjugates, including gangliosides GD1a and GT1b (18)(19)(20)(21). Although the axonal receptor for CSPGs is unknown, its glycosaminoglycan chains are required for inhibiting axon outgrowth (22).…”

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confidence: 99%

“…These findings provide opportunities to block ARI function by infusing enzymes to injury sites. Chondroitinase ABC digests the glycosaminoglycan chains of CSPGs (22), phosphatidylinositol-specific phospholipase C (PI-PLC) removes NgRs from the axon surface and OMgp from myelin (23,24), and sialidase destroys the glycan-binding determinant of MAG (18,21,25). We report the effect of each of these enzymes on spinal axon outgrowth into peripheral nerve grafts in vivo.…”

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confidence: 99%

Sialidase enhances spinal axon outgrowth in vivo

Yang

Lorenzini

Vajn

et al. 2006

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

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The adult CNS is an inhibitory environment for axon outgrowth, severely limiting recovery from traumatic injury. This limitation is due, in part, to endogenous axon regeneration inhibitors (ARIs) that accumulate at CNS injury sites. ARIs include myelin-associated glycoprotein, Nogo, oligodendrocyte-myelin glycoprotein, and chondroitin sulfate proteoglycans (CSPGs). Some ARIs bind to specific receptors on the axon growth cone to halt outgrowth. Reversing or blocking the actions of ARIs may promote recovery after CNS injury. We report that treatment with sialidase, an enzyme that cleaves one class of axonal receptors for myelinassociated glycoprotein, enhances spinal axon outgrowth into implanted peripheral nerve grafts in a rat model of brachial plexus avulsion, a traumatic injury in which nerve roots are torn from the spinal cord. Repair using peripheral nerve grafts is a promising restorative surgical treatment in humans, although functional improvement remains limited. To model brachial plexus avulsion in the rat, C8 nerve roots were cut flush to the spinal cord and a peroneal nerve graft was inserted into the lateral spinal cord at the lesion site. Infusion of Clostridium perfringens sialidase to the injury site markedly increased the number of spinal axons that grew into the graft (2.6-fold). Chondroitinase ABC, an enzyme that cleaves a different ARI (CSPGs), also enhanced axon outgrowth in this model. In contrast, phosphatidylinositol-specific phospholipase C, which cleaves oligodendrocyte-myelin glycoprotein and Nogo receptors, was without benefit. Molecular therapies targeting sialoglycoconjugates and CSPGs may aid functional recovery after brachial plexus avulsion or other nervous system injuries and diseases.axon regeneration ͉ brachial plexus injury ͉ chondroitinase ABC ͉ gangliosides ͉ spinal cord injury

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Myelin-Associated Glycoprotein Inhibits Axonal Regeneration from a Variety of Neurons via Interaction with a Sialoglycoprotein

Cited by 168 publications

References 0 publications

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

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

Sialidase enhances spinal axon outgrowth in vivo

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