ReviewMyelin associated inhibitors: A link between injury-induced and experience-dependent plasticity☆
Introduction
Spinal cord injuries (SCIs) have classically been regarded as devastating injuries from which there is no recovery due to restricted axonal growth in the adult central nervous system (CNS). This notion has been modified in recent years by reports of limited recovery in patients suffering from a variety of SCIs (Burns et al., 1997, Geisler et al., 2001). Understanding the basis of recovery, as well as the systems that limit growth in the CNS, has been the goal of a century of research. While our understanding remains incomplete, myriad studies have described how injured neurons can be stimulated to grow, overcome physical and chemical barriers, and make functional connections. Here we focus on studies demonstrating the role of myelin-associated inhibitors (MAIs) in restricting axonal growth in the CNS with particular emphasis on the Nogo–Nogo Receptor axis.
Pioneering work demonstrated that MAIs inhibit axonal regeneration; however, their physiological role remained unclear. Importantly, when MAIs have been antagonized in animal models of SCI, functional recovery exceeds frank axonal regeneration per se. The search for an anatomical correlate to increased functional recovery led to the insight that MAIs limit a wide spectrum of injury-induced growth that includes axonal regeneration, sprouting, and plasticity. Genetic dissection of the roles played by MAIs in SCI led to two important insights. First, SCI recovery is dependent on both regenerative and non-regenerative anatomical growth, significantly complicating our analysis of neurological recovery from CNS damage. Second, the existence of an inhibitory system regulating a wide spectrum of growth emphasizes the physiological role of MAIs, and led to the appreciation of a common regulatory system for both experience and activity-dependent plasticity. The existence of a shared system for limiting anatomical reorganization in the naïve and injured CNS blurs the distinction between translational injury repair studies and more “basic” plasticity studies.
Section snippets
Axonal regeneration
Regeneration is a remarkable feat that requires extensive coordinated biology: the lesioned axon must survive, find permissive cues for growth, receive appropriate trophic support, extend towards relevant synaptic targets, and ultimately make functional connections. Cajal first described the ability of PNS (peripheral nervous system), but not CNS, neurons to regenerate in 1928 (Cajal, 1991). Despite this early observation, nearly 60 years passed before a clear picture emerged as to why
Regeneration, sprouting, and plasticity: a continuum of repair
A wide spectrum of inhibitors has been observed to limit neurite outgrowth in vitro, and when antagonized in animal models of SCI, cause significant regeneration of severed axons in vivo. Nonetheless, the extent of the observed regeneration alone does not explain the levels of functional recovery observed in rodent and primate models of SCI. In classic spinal hemisection models targeting the corticospinal tract in rodents and primates, significant neurological recovery is observed despite scant
Myelin and plasticity in the naïve brain
The search for inhibitors of CNS regeneration led to the discovery of MAIs that limit a wide spectrum of injury-induced anatomical growth. Injury, however, is not the only stimulus for plasticity. The understanding that MAIs limit a wide spectrum of injury-induced anatomical plasticity led investigators to test if this system also limits plasticity in the uninjured CNS. It has now been demonstrated that MAIs limit both experience and activity dependent plasticity in the adult mammalian brain,
Injury, plasticity, and MAIs
The potential for recovery after a SCI is limited by the inhibitory environment of the mature CNS. The identification of these inhibitors and their receptors has led to the understanding that regeneration is a point along a continuum of anatomic growth that includes sprouting and plasticity. This spectrum represents distinct but fundamentally related forms of cytoskeletal rearrangements; the principle difference is magnitude. Given their demonstrated roles in regulating cytoskeletal dynamics (
Acknowledgments
F.A. is supported by an Institutional Medical Scientist Training Program from the N.I.H, NIH MSTP TG 2T32GM07205. This work was supported by the grants from the Christopher and Dana Reeve Foundation, the Wings for Life Foundation and the Dr. Ralph and Marion Falk Medical Research Trust to S.M.S., and from the National Institutes of Health to W.B.J.C. and S.M.S.
References (110)
Lack of evidence that myelin-associated glycoprotein is a major inhibitor of axonal regeneration in the CNS
Neuron
(1995)Recovery of ambulation in motor-incomplete tetraplegia
Arch. Phys. Med. Rehabil.
(1997)Response to correspondence: Kim et al., “axon regeneration in young adult mice lacking Nogo-A/B.” Neuron 38, 187–199
Neuron
(2007)- et al.
Axonal growth therapeutics: regeneration or sprouting or plasticity?
Trends Neurosci.
(2008) BDNF regulates the maturation of inhibition and the critical period of plasticity in mouse visual cortex
Cell
(1999)A multi-domain fragment of nogo-a is a potent inhibitor of cortical axon regeneration via nogo receptor 1
J. Biol. Chem.
(2011)Assessment of functional recovery and axonal sprouting in oligodendrocyte-myelin glycoprotein (OMgp) null mice after spinal cord injury
Mol. Cell. Neurosci.
(2008)NOGO mRNA expression in adult and fetal human and rat nervous tissue and in weight drop injury
Exp. Neurol.
(2001)Axon regeneration in young adult mice lacking Nogo-A/B
Neuron
(2003)Nogo-C is sufficient to delay nerve regeneration
Mol. Cell. Neurosci.
(2003)
Nogo-66 receptor prevents raphespinal and rubrospinal axon regeneration and limits functional recovery from spinal cord injury
Neuron
Assessing spinal axon regeneration and sprouting in Nogo- , MAG- , and OMgp-deficient mice
Neuron
Transgenic inhibition of Nogo-66 receptor function allows axonal sprouting and improved locomotion after spinal injury
Mol. Cell. Neurosci.
Identification of myelin-associated glycoprotein as a major myelin-derived inhibitor of neurite growth
Neuron
Neuronal Nogo-A modulates growth cone motility via Rho-GTP/LIMK1/Cofilin in the unlesioned adult nervous system
J. Biol. Chem.
A novel role for myelin-associated glycoprotein as an inhibitor of axonal regeneration
Neuron
Paired immunoglobulin-like receptor B knockout does not enhance axonal regeneration or locomotor recovery after spinal cord injury
J. Biol. Chem.
A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors
Neuron
Regulation of spine and synapse formation by activity-dependent intracellular signaling pathways
Curr. Opin. Neurobiol.
TAJ/TROY, an orphan TNF receptor family member, binds Nogo-66 receptor 1 and regulates axonal regeneration
Neuron
Systemic deletion of the myelin-associated outgrowth inhibitor Nogo-A improves regenerative and plastic responses after spinal cord injury
Neuron
PirB is a functional receptor for myelin inhibitors of axonal regeneration
Science
Oligodendrocytes arrest neurite growth by contact inhibition
J. Neurosci.
The injured spinal cord spontaneously forms a new intraspinal circuit in adult rats
Nat. Neurosci.
Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins
EMBO J.
Immunohistological localization of the adhesion molecules L1, N-CAM, and MAG in the developing and adult optic nerve of mice
J. Comp. Neurol.
Chondroitinase ABC promotes functional recovery after spinal cord injury
Nature
Recovery from spinal cord injury mediated by antibodies to neurite growth inhibitors
Nature
Regeneration of lesioned corticospinal tract fibers in the adult rat induced by a recombinant, humanized IN-1 antibody fragment
J. Neurosci.
Genetic variants of Nogo-66 receptor with possible association to schizophrenia block myelin inhibition of axon growth
J. Neurosci.
Genetic variants of Nogo-66 Receptor with possible association to schizophrenia block myelin inhibition of axon growth
J. Neurosci.
Application of neutralizing antibodies against NI-35/250 myelin-associated neurite growth inhibitory proteins to the adult rat cerebellum induces sprouting of uninjured purkinje cell axons
J. Neurosci.
Functional axonal regeneration through astrocytic scar genetically modified to digest chondroitin sulfate proteoglycans
J. Neurosci.
MAG and OMgp synergize with Nogo-A to restrict axonal growth and neurological recovery after spinal cord trauma
J. Neurosci.
Cajal's Degeneration and Regeneration of the Nervous System
Two membrane protein fractions from rat central myelin with inhibitory properties for neurite growth and fibroblast spreading
J. Cell Biol.
Oligodendrocyte myelin glycoprotein does not influence node of ranvier structure or assembly
J. Neurosci.
Nogo-A is a myelin-associated neurite outgrowth inhibitor and an antigen for monoclonal antibody IN-1
Nature
The Nogo-66 Receptor NgR1 is required only for the acute growth cone-collapsing but not the chronic growth-inhibitory actions of myelin inhibitors
J. Neurosci.
Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins
J. Neurosci.
The role of visual experience in the development of columns in cat visual cortex
Science
Axonal elongation into peripheral nervous system “bridges” after central nervous system injury in adult rats
Science
Nogo-A-deficient mice reveal strain-dependent differences in axonal regeneration
J. Neurosci.
Regenerating corticospinal fibers in the Marmoset (Callitrix jacchus) after spinal cord lesion and treatment with the anti-Nogo-A antibody IN-1
Eur. J. Neurosci.
Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration
Nature
Truncated soluble Nogo receptor binds Nogo-66 and blocks inhibition of axon growth by myelin
J. Neurosci.
Rho kinase inhibition enhances axonal regeneration in the injured CNS
J. Neurosci.
Nogo-A-specific antibody treatment enhances sprouting and functional recovery after cervical lesion in adult primates
Nat. Med.
Anti-Nogo-A antibody treatment enhances sprouting of corticospinal axons rostral to a unilateral cervical spinal cord lesion in adult macaque monkey
J. Comp. Neurol.
Anti-Nogo-A antibody treatment promotes recovery of manual dexterity after unilateral cervical lesion in adult primates — re-examination and extension of behavioral data
Eur. J. Neurosci.
Cited by (117)
Immunohistochemistry for the non-human primate
2023, Spontaneous Pathology of the Laboratory Non-human PrimateSpinal cord injury
2022, Neurobiology of Brain Disorders: Biological Basis of Neurological and Psychiatric Disorders, Second EditionTranslational perspective: Neuroregenerative strategies and therapeutics for traumatic spinal cord injury
2022, Neural Repair and Regeneration after Spinal Cord Injury and Spine TraumaNeuroimmune interactions and immunoengineering strategies in peripheral nerve repair
2022, Progress in NeurobiologyCitation Excerpt :The antibody IN-1 binds to Nogo and blocks its expression, resulting in enhanced axonal regeneration and improved functional recovery (Chen et al., 2000; Fawcett and Asher, 1999). Likewise, MAG is expressed in myelin and can also inhibit some, but not all, axonal growth cones (Akbik et al., 2012; Fawcett and Asher, 1999). During Wallerian degeneration, Schwann cells break down myelin during the first 5–7 days after injury and package myelin into discrete ovoid segments (Perry et al., 1995).
Nogo BACE jumps on the exosome
2020, Journal of Biological Chemistry
- ☆
Disclosure: S.M.S. is a co-founder of Axerion Therapeutics seeking to develop PrP and NgR therapies.