Review
Repulsive factors and axon regeneration in the CNS

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Abstract

During the past year, a major advance in the study of axon regeneration was the molecular cloning of Nogo. The expression of Nogo protein by CNS myelin may be a major factor in the failure of CNS axon regeneration. The effect of disrupting Nogo-dependent axon inhibition can now be studied conclusively. In related work, immunization with a Nogo-containing CNS myelin preparation was shown to promote regeneration and dramatic functional recovery after spinal cord trauma.

Introduction

Axons in the mammalian central nervous system (CNS) do not spontaneously regenerate following injury and consequently there is little functional recovery. This differs from the response of injured axons in the adult peripheral nervous system (PNS), which do regenerate following injury. However, it is clear that adult CNS axons are not intrinsically incapable of regeneration. When provided with a suitable environment, injured CNS axons can extend for long distances through growth-permissive peripheral nerve grafts [1]. Multiple factors contribute to the lack of spontaneous regeneration in the CNS. Injured CNS neurons fail to reexpress at least some of the growth-associated proteins that are expressed during development and during successful regeneration [2]. Furthermore, axon-growth-promoting cues such as neurotrophic factors, which mediate cell survival and neurite outgrowth during development, are often absent following injury in the adult CNS. In addition to the absence of positive cues, a number of growth-inhibitory factors have been identified at the site of the CNS lesion (Table 1). The distal tip of the injured axon is exposed to both myelin-associated inhibitors and a growth-inhibitory glial scar (Fig. 1). This review will focus on the most recent advances in the identification and mode of action of inhibitory molecules that are present following injury to the adult CNS.

Section snippets

Myelin-associated inhibitors and the glial scar

The relative contributions of the glial scar and myelin-associated inhibitors remain a subject of study. Multiple inhibitors have been identified in CNS myelin including Nogo [3], myelin-associated glycoprotein (MAG) [4], chondroitin sulfate proteoglycan (CSPG) [5radical dot] and arretin [6]. Not all axonal growth is abolished by these molecules. Experiments by Silver and colleagues have demonstrated that microtransplanted adult dorsal root ganglion (DRG) neurons are capable of growing on intact or

Nogo

Of the multiple inhibitory components identified in CNS myelin, the most extensively studied is NI35 and the antigenically related NI-250 (Nogo-A) [13]. The interest in this protein stems principally from the effects of a monoclonal antibody (IN-1) that was raised against NI-250 (Nogo-A) and recognizes both NI35 and NI-250 (Nogo-A). Application of IN-1 to a lesion site in vivo enhances regrowth of CST fibers and promotes some functional recovery [14]. The identity of this protein remained

Intracellular signaling

Treatment of the injured neuronal cell body by providing antagonists to receptor proteins or by modifying intracellular signaling pathways is a relatively new strategy in the battle against neurite outgrowth inhibition. Historically, strategies to overcome inhibition have focused on modifying the inhibitory environment at the distal aspect of the injured neurite. However, injured cell bodies may represent a more accessible target for treatment following injury, and inhibitory molecules may

Embryonic axon repulsion and adult axon regeneration

A number of families of molecules with repulsive roles during development have been identified, and their potential roles in regeneration are now being studied. The semaphorin family of secreted and transmembrane glycoproteins function as repulsive molecules during development [31], and studies examining their expression levels and localization in models of nerve injury suggest that they may also play a role in regenerative growth. Sema3D is expressed by oligodendrocytes and is present in both

Conclusions

In summary, the cloning of Nogo [15, [16, [17 represents a major step in our understanding of myelin-dependent inhibition following injury. The promising regrowth and functional recovery observed with the IN-1 antibody suggests that disruption of Nogo ligand–receptor interactions may have dramatic effects on neurite outgrowth following injury. A more complete analysis of Nogo receptor components and intracellular substrates should greatly enhance our understanding of neurite outgrowth

Acknowledgements

This work was supported by grants to SM Strittmatter from the National Institutes of Health and the Christopher Reeve Paralysis Foundation. AE Fournier is a Formation de Chercheurs et l'Aide à la Recherche (FCAR) research fellow. SM Strittmatter is an investigator of the Patrick and Catherine Weldon Donaghue Medical Research Foundation.

References and recommended reading

Papers of particular interest, published within the annual period of review,have been highlighted as:

radical dotof special interest

radical dotradical dotof outstanding interest

Now in press

The work refererred to as ‘Fournier AE, Grandpre T, Strittmatter SM, unpublished data’ is now in press.

Fournier AE, Grandpre T, Strittmatter SM: Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration. Nature 2001, 409:341-346.

The authors report the identification of a receptor mediating Nogo66 inhibition. A brain-specific, leucine-rich-repeat protein with high affinity for soluble Nogo66 was identified and termed Nogo66 receptor (Ng66R). Cleavage of the Ng66R and other

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