ReviewRepulsive factors and axon regeneration in the CNS
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) [5] 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:
of special interest
of 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
References (46)
- et al.
Identification and characterization of a bovine neurite growth inhibitor (bNI-220)
J Biol Chem
(1998) - et al.
Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite outgrowth
Neuron
(1994) - et al.
A therapeutic vaccine approach to stimulate axon regeneration in the adult mammalian spinal cord
Neuron
(1999) - et al.
A potent inhibitor of neurite outgrowth that predominates in the extracellular matrix of reactive astrocytes
Int J Dev Neurosci
(1996) - et al.
Chondroitin sulfate proteoglycan immunoreactivity increases following spinal cord injury and transplantation
Exp Neurol
(1999) - et al.
Antibody against myelin-associated inhibitor of neurite growth neutralizes non-permissive substrate properties of CNS white matter
Neuron
(1988) - et al.
cAMP dependent growth cone guidance by netrin-1
Neuron
(1997) - et al.
Prior exposure to neurotrophins blocks inhibition of axonal regeneration by MAG and myelin via a cAMP-dependent mechanism
Neuron
(1999) - et al.
Rho family small GTP-binding proteins in growth cone signaling
Curr Opin Neurobiol
(1997) - et al.
Elevation of intracellular cAMP inhibits RhoA activation and integrin-dependent leukocyte adhesion induced by chemoattractants
J Biol Chem
(1997)
Regeneration of dorsal column fibers into and beyond the lesion site following adult spinal cord injury
Neuron
Long axon growth from embryonic neurons transplanted into myelinated tracts of the adult rat spinal cord
Brain Res
The semaphorin genes encode a family of transmembrane and secreted growth cone guidance molecules
Cell
A family of molecules related to collapsin in the embryonic chick nervous system
Neuron
Expression of the gene encoding the chemorepellent Semaphorin III is induced in the fibroblast component of neural scar tissue formed following injuries of adult but not neonatal CNS
Mol Cell Neurosci
The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans
Neuron
Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance
Cell
Slit is the midline repellent for the robo receptor in Drosophila
Cell
Biochemical purification of a mammalian slit protein as a positive regulator of sensory axon elongation and branching
Cell
Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons
Cell
Netrin-1 and peripheral nerve regeneration in the adult rat
Exp Neurol
Induction of Eph B3 after spinal cord injury
Exp Neurol
Axonal elongation in peripheral nervous system bridges after central nervous system injury in adult rats
Science
Cited by (163)
Macrophage biology in the peripheral nervous system after injury
2019, Progress in NeurobiologyCanine olfactory ensheathing cells from the olfactory mucosa can be engineered to produce active chondroitinase ABC
2016, Journal of the Neurological SciencesSpinal Cord Injury and Regeneration: A Critical Evaluation of Current and Future Therapeutic Strategies
2014, Pathobiology of Human Disease: A Dynamic Encyclopedia of Disease MechanismsHSV-mediated gene transfer of C3 transferase inhibits Rho to promote axonal regeneration
2012, Experimental NeurologyCitation Excerpt :Trauma to the brachial plexus often results in devastating injuries, with only partial restoration of shoulder function despite best currently available therapies (Giuffre et al., 2010). Peripheral axons are capable of regeneration, but elongation of the central sensory afferents and motor efferents is blocked by the growth inhibitory effects of chondroitin sulfate proteoglycans (CSPG) in the glial scar, and myelin proteins NogoA, myelin associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgP) that through their cognate neuronal receptors activate axonal Rho GTPase to inhibit neurite extension (Filbin, 2003; Fournier and Strittmatter, 2001; Huber and Schwab, 2000; Snow et al., 1990; Wang et al., 2002). The Rho GTPases are a family of monomeric G-proteins that transduce extracellular signals regulating actin cytoskeleton and microtubule polymerization.