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

Nature Reviews Neuroscience volume 4, pages 703–713 (2003)Cite this article

A Correction to this article was published on 01 December 2003

Key Points

  • The fact that the adult mammalian central nervous system (CNS) does not regenerate after injury was recognized as early as 1550 BC. There are two main obstacles to regeneration — inhibitors within myelin, and the formation of a glial scar. This review will discuss what is known about the myelin inhibitors, and how their effects might be overcome.

  • Three inhibitors of axonal regeneration have been identified in myelin – Nogo, myelin-associated glycoprotein (Mag) and oligodendrocyte myelin glycoprotein (Omgp). All of these proteins induce growth cone collapse and inhibit neurite outgrowth.

  • In 2001, Strittmatter and colleagues cloned the Nogo receptor (Ngr), which they identified as a binding partner of the Nogo domain Nogo-66. It has since been found that Mag and Omgp also bind to this receptor. Ngr cannot transduce signals across the membrane, as it has no transmembrane and cytoplasmic domains, so it seems to use the p75 neurotrophin receptor (p75NTR) as a transducing partner.

  • Members of the Rho family of small GTPases have been implicated in myelin's inhibitory effects. Rho has been suggested to interact directly with p75NTR, and activation of p75NTR initiates various signalling cascades. Some of these cascades might run in parallel with the Rho pathway to bring about inhibition when myelin inhibitors bind to the Ngr–p75NTR complex.

  • Two approaches might be used to overcome inhibitors and encourage regeneration. First, the inhibitors and/or their receptors could be blocked with antibodies or peptides. Second, the intrinsic state of the neuron could be changed, such that it no longer recognizes the environment as inhibitory. Elevation of cyclic AMP inside the injured neuron has been shown to overcome inhibition by Mag and myelin.

  • To identify genes and proteins that are required for regeneration, it is useful to look for genes that are upregulated in systems that regenerate spontaneously after injury. Studies have focused on two such situations — neonatal spinal neurons, which can regenerate to produce complete functional recovery, and regeneration of the CNS branch of dorsal root ganglion neurons after the peripheral branch has been lesioned.

  • Overcoming inhibitors of regeneration in myelin is only one aspect of a complex problem. Even if axons can be induced to grow across the lesion site before the glial scar forms, they still need to be directed back to their correct destination and make functional synapses. The first step is to get the axons to grow, and the last few years have seen enormous advances in this respect.

Abstract

Recent studies have expanded our knowledge, at the molecular level, of how myelin inhibits axonal regeneration after injury to the mammalian central nervous system. Several inhibitors have been identified that seem to signal inhibition through the same receptor complex. New molecular information has also accumulated on how the neuron can be changed intrinsically to overcome myelin inhibitors. Together, these important advances in the field have identified many new targets for therapeutic intervention to encourage nerve regeneration after spinal cord or brain injury.

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Figure 1: Structures of three inhibitors of axonal regeneration identified in myelin.
Figure 2: Nogo-66, Mag and Omgp interact with the same receptor complex.
Figure 3: Model of signalling inhibition through the Ngr–p75NTR receptor complex.
Figure 4: Elevation of cyclic AMP mimics the effects of a peripheral conditioning lesion on dorsal column regeneration.

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Acknowledgements

This review is dedicated to the memory of N. Kimura. I thank R. Persell for critically reading this manuscript and T. Spencer for creating the figures. Funding was provided by the NIH/NINDS/RCMI/SNRP, the National Multiple Sclerosis Society, USA and the New York State Spinal Cord Initiative.

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  1. Department of Biological Sciences, Hunter College, City University of New York, 695 Park Avenue, New York, 10021, New York, USA

    Marie T. Filbin

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  1. Marie T. Filbin
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DATABASES

LocusLink

Gap43

Mag

Nogo-A

Ngr

Omgp

p75NTR

Sprrp1a

Glossary

LECTINS

Sugar-binding proteins that tend to agglutinate cells.

PARANODAL LOOPS

Concertina-shaped folds of myelin, which flank the nodes of Ranvier.

SCHMIDT-LANTERMAN INCISURES

Funnel-shaped interruptions in the myelin sheath that were shown by electron microscopy to correspond to strands of cytoplasm separating two otherwise fused myelinating cell membranes.

GLYCOSYL PHOSPHATIDYLINOSITOL

A post-translational modification, the function of which is to attach proteins to the exoplasmic leaflet of membranes, possibly to specific domains therein. The anchor is made of one molecule of phosphatidylinositol to which a carbohydrate chain is linked through the C6 hydroxyl of the inositol, and is attached to the protein through an ethanolamine phosphate moiety.

IGM ANTIBODY

An immunoglobulin molecule that consists of five immunoglobulin G-type monomers, joined together by J chains to form a cyclic pentamer. During an immune response, IgM is usually produced before IgG, and forms the first line of defence.

NODE OF RANVIER

A region of exposed plasma membrane in a myelinated axon. The nodes propagate action potentials by saltatory conduction, and they contain high concentrations of voltage-gated ion channels.

DOMINANT NEGATIVE

A mutant molecule that can interfere with the normal molecule, knocking out its activity

GANGLIOSIDE

An anionic glycosphingolipid that carries one or more sialic acid residues, in addition to other sugar residues.

GENE TRAPPING

A mutation strategy that makes use of insertion vectors to trap or isolate transcripts from flanking genes. The inserted sequence acts as a tag from which to clone the mutated gene.

DORSAL ROOT GANGLION

The cell bodies of sensory neurons are collected together in paired ganglia that lie alongside the spinal cord. These cell bodies are surrounded by satellite glial cells, which have much in common with the Schwann cells that ensheath peripheral axons. Very few synapses have been observed in these ganglia.

SMALL GTPASE PROTEINS

A family of proteins that can hydrolyse GTP, which includes Rac, Rab, Ran, Rad, Rho and others. They subserve multiple cellular functions; for example, Rho and Rac are involved in the control of the cytoskeleton.

PERTUSSIS TOXIN

The causative agent of whooping cough, pertussis toxin causes the persistent inactivation of Gi proteins by catalysing the ADP-ribosylation of the α-subunit.

POLYAMINES

Organic compounds that contain two or more amino groups. Putrescine, spermine and spermidine are prime examples.

INWARDLY RECTIFYING K+ CHANNELS

Potassium channels that allow long depolarizing responses, as they close during depolarizing pulses and open with steep voltage dependence on hyperpolarization. They are called inward rectifiers because current flows through them more easily into than out of the cell.

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Filbin, M. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nat Rev Neurosci 4, 703–713 (2003). https://doi.org/10.1038/nrn1195

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