Damage to the adult CNS leads to persistent deficits owing to the inability of CNS axons to regenerate after injury. This regeneration failure is attributable to the reduced intrinsic growth ability of mature neurons and extrinsic inhibitory influences from the glial environment, such as inhibitory molecules in CNS myelin and chondroitin sulphate proteoglycans (CSPGs) from the glial scar.
Many myelin-associated inhibitors have been identified using in vitro assays, including Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp). Repulsive guidance cues that are important during development, such as ephrin B3 and semaphorin 4D, might also persist in the adult and limit axon growth.
CSPGs expressed by reactive astrocytes can inhibit axon regeneration through their protein core or glycosaminoglycan moieties. Although both CNS myelin and CSPGs are likely to contribute to regeneration failure, their relative importance remains uncertain.
Although receptor mechanisms for CSPGs are not known, most myelin inhibitors signal through a common receptor complex that consists of the Nogo-66 receptor (NgR) and its co-receptors p75 or TROY and LINGO1. Recent evidence from genetic deletion studies, however, suggests that there are also NgR-independent signalling pathways.
Common intracellular mechanisms probably mediate both CNS myelin and CSPG-based inhibition. The best-characterized pathway involves the small GTPase RhoA and its effector Rho-associated kinase (ROCK), which can regulate the actin cytoskeleton. Calcium-related signals, including protein kinase C and epidermal growth factor (EGFR), might also be involved in these inhibitory pathways.
Many in vivo studies have targeted these inhibitory ligands, receptors and downstream components to promote regeneration after spinal cord injury. Whereas some pharmacological and dominant-negative approaches have shown promise, most knockout studies have met with limited success. These results demonstrate the complexity and cross-compensation between the different inhibitory influences, and the potential existence of as yet unidentified mechanisms.
Recent reports are revealing intriguing parallels between the mechanisms that prevent axon repair after CNS injury, and those that limit experience-dependent plasticity. Even in the absence of long-distance axon regeneration, recovery from CNS injuries might benefit from local sprouting and structural plasticity similar to the way in which sensory experience fine-tunes neural circuits during the critical period.
Alleviating glial inhibition might not only promote the regrowth of damaged axons, but might also enhance recovery through local compensatory sprouting. Combinatorial approaches that target multiple inhibitory pathways and promote the intrinsic growth ability of neurons might be necessary to achieve significant long-distance regeneration.
Damage to the adult CNS often leads to persistent deficits due to the inability of mature axons to regenerate after injury. Mounting evidence suggests that the glial environment of the adult CNS, which includes inhibitory molecules in CNS myelin as well as proteoglycans associated with astroglial scarring, might present a major hurdle for successful axon regeneration. Here, we evaluate the molecular basis of these inhibitory influences and their contributions to the limitation of long-distance axon repair and other types of structural plasticity. Greater insight into glial inhibition is crucial for developing therapies to promote functional recovery after neural injury.
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We wish to thank M. Hou for critical reading of this manuscript. Our work is supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS), the McKnight foundation and the US National Multiple Sclerosis Society.
The authors declare no competing financial interests.
- Dystrophic growth cones
Unusually shaped nerve terminals that are characterized by small globular clusters or multivesicular sacs found on the distal ends of regenerating axons in a glial scar environment.
- Dorsal root ganglia
(DRG). Ganglia that are found beside the spinal cord in which the cell bodies of sensory neurons are located. The bipolar neurons send a central axon through the spinal cord and another process to the PNS.
Glial cells that elaborate myelin in the CNS. Unlike Schwann cells in the PNS that myelinate single axons, oligodendrocytes typically ensheath several processes at once.
The most abundant glial cell in the CNS, with a star-shaped cell body and broad end-feet on their processes. Astrocytes are thought to have nutritive functions, as well as roles in maintaining the blood–brain barrier and extracellular milieu.
- Glial scar
A physical and molecular barrier to regeneration that develops at CNS lesion sites, consisting primarily of reactive astrocytes, along with extracellular matrix molecules such as CSPGs.
- Growth cone
A motile actin-supported extension of a developing axon that can respond to external cues to guide its movement. Exposure to some repulsive guidance cues and many myelin-associated inhibitors leads to the collapse of this broad-shaped structure.
- Alternative splicing
A post-transcriptional process through which a pre-mRNA molecule, containing several introns and exons, can lead to different functional mRNA molecules, and consequently proteins, that originate from a single gene.
A glycosylphosphatidylinositol (GPI) linkage, located at the carboxy termini of proteins without hydrophobic transmembrane regions, that can insert into the cell membrane. They might be released from the membrane by treatment with phospholipase C.
- Corticospinal tract
(CST). Axon fibres that originate from pyramidal neurons in layer 5 of the cerebral cortex and synapse on motor and interneurons in the spinal cord. This tract mediates motor functions and is commonly used for CNS injury models.
- Dorsal root entry zone
(DREZ). The interface between the CNS and PNS where sensory afferents from dorsal root ganglia enter the spinal cord during development.
The area of secondary injury surrounding a CNS lesion epicentre.
- Dorsal rhizotomy
A transection of sensory nerve fibres in the dorsal root at its point of entry into the spinal cord.
- Rho-guanine dissociation inhibitor
(Rho-GDI). An inhibitory regulator of the Rho small G-protein family that can bind to RhoA and maintain it in an inactive state.
- Dorsal columns
Axon fibres that consist of the central processes of medium-diameter sensory dorsal root ganglia neurons that project up to dorsal column nuclei in the medulla.
- Raphespinal tract
Serotonin-containing fibres originating from caudal raphe nuclei in the brainstem to modulate sensory inputs such as pain.
- Rubrospinal tract
Axon fibres that are functionally related to corticospinal tracts, that originate from the caudal red nucleus and terminate on motor neurons in the spinal cord.
- Preconditioning injury
A lesion of the peripheral branch of bipolar sensory neurons in dorsal root ganglia that can promote the subsequent regeneration of their central axons in the spinal cord after nerve transection at a later time point.
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Cite this article
Yiu, G., He, Z. Glial inhibition of CNS axon regeneration. Nat Rev Neurosci 7, 617–627 (2006). https://doi.org/10.1038/nrn1956
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