Trends in Molecular Medicine
Research FocusThe Nogo receptor complex: confining molecules to molecular mechanisms
Section snippets
Myelin inhibition of axonal regeneration: Nogo-A
Axon regeneration in the adult CNS is at least in part controlled by inhibitors that are located in the myelin – a concept that has been developed and established by the pioneering work of Schwab and Caroni [1]. They identified a protein, which was later termed Nogo-A, that is the first and most prominent axon-growth inhibitor located in the myelin. As a result of an intense search [2], two inhibitory domains of Nogo-A were found: the Nogo-A544–725 domain (also known as Amino-Nogo-A), which is
New members of the trimeric NgR1 complex: p75NTR, LINGO-1 and TROY/TAJ
Three membrane proteins have been described to form a receptor complex with NgR1: the low-affinity neurotrophin receptor p75, LINGO-1 [13] and TROY (also known as TAJ) 14, 15 (Figure 1B). TROY/TAJ, a p75-neurotrophin-receptor (p75NTR)-related member of the tumor necrosis factor (TNF) family, influences myelin-derived inhibitory signals of neuronal fiber (axonal) outgrowth and/or regeneration 14, 15. Activation of the NgR1 complex abrogates axonal outgrowth and nerve-fibre regeneration. However,
Intramembrane proteolysis: p75NTR cleavage by secretases
A new mechanism of NgR1-mediated intra-neuronal signal integration has been unravelled by modifying one of the transducing components, p75NTR (Figure 1b). Upon stimulation with MAG, the NgR1 complex triggers intramembrane proteolysis (RIP) of the co-receptor p75 [21]. p75NTR is sequentially cleaved by α-secretase and γ-secretase in a protein-kinase-C (PKC)-dependent manner. The cleaved cytoplasmic product of p75NTR – the intracellular domain (ICD) – is necessary for MAG-induced inhibition of
Epidermal growth factor receptor: an unexpected candidate of axoplasmic second-messenger systems
It is still unclear how second-messenger mechanisms are integrated via the inhibitory myelin-derived signal that converges finally into intra-axoplasmic Rho activation. Although it is known that, as an early response to myelin inhibitor contact, cytoplasmic Ca2+ levels rise through release from intracellular storage and influx across the plasma membrane, triggered second-messenger mechanisms are not well understood. He and colleagues [26] have demonstrated that binding of myelin inhibitors to
Concluding remarks
The inhibitory environment and the axotomized neurite are subject to reactive, dynamic changes impinging on fragile and tightly controlled molecular processes such as ligand–receptor interaction and inhibitor-elicited signalling 28, 29. Thus, these findings await to be translated into the lesion pathophysiology in vivo where further unidentified compensatory, redundant pathways might be present. Nevertheless, the identification of new inhibitory molecules, accessory proteins, multi-molecular
Acknowledgements
We thank Dr. N. Chiang and Dr. S.P. Colgan (Center for Experimental Therapeutics, Brigham and Women's Hospital, Boston, USA) for thoughtful comments. This work was supported by the Wings for Life Spinal Cord Research Foundation. J.M.S. was awarded by an international poste-rouge scholarship of the Centre National de la Recherche Scientifique (CNRS, France) and is at present a research fellow supported by the German Research Council (DFG, 1164/1–1).
References (29)
- et al.
Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro
J. Neurosci.
(1988) Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS
Nat. Rev. Neurosci.
(2003)Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions
J. Neurosci.
(2003)Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration
Nature
(2001)Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins
EMBO J.
(2003)The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein
J. Neurosci.
(2005)Nogo-A, -B, and -C are found on the cell surface and interact together in many different cell types
J. Biol. Chem.
(2005)Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist
J. Neurosci.
(2005)Targeting the Nogo receptor to treat central nervous system injuries
Nat. Rev. Drug Discov.
(2003)The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion
J. Neurosci.
(2003)
Ephrin-B3 is a myelin-based inhibitor of neurite outgrowth
Proc. Natl. Acad. Sci. U. S. A.
RGMa inhibition promotes axonal growth and recovery after spinal cord injury
J. Cell Biol.
LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex
Nat. Neurosci.
A TNF receptor family member, TROY, is a coreceptor with Nogo receptor in mediating the inhibitory activity of myelin inhibitors
Neuron
Cited by (30)
A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders
2015, Neuroscience and Biobehavioral ReviewsCitation Excerpt :The Epidermal Growth Factor Receptor (EGFR), also known as ErbB-1, triggers the activation of the Phosphoinositide 3-kinase (PI3-K)/Akt signaling pathway leading to DNA synthesis and cell proliferation including neuronal survival and growth (Brunet et al., 2001; Inoue et al., 2007; Oda et al., 2005). The binding of myelin inhibitors to NgR, has been shown to trigger phosphorylation of EGFR in a Ca2+ dependent manner (Koprivica et al., 2005), however EGFR activation by its own ligand, Epidermal Growth Factor (EGF), is not sufficient to inhibit axonal-outgrowth (Koprivica et al., 2005), thus it is reasonable to speculate that receptor transactivation of EGFR by the NgR complex may activate a different set of signaling cascades (Schwab et al., 2006). More recently studies have shown that some LRR Ig-containing proteins are able to influence growth factors by modulating pathways related to EGFR signaling (Goldoni et al., 2007; Gur et al., 2004), indicating that it may in fact be due to Lingo-1 signaling that NgR is able to affect EGFR.
Non-canonical actions of Nogo-A and its receptors
2015, Biochemical PharmacologyLoss of Nogo-A-expressing neurons in a rat model of Parkinson's disease
2015, NeuroscienceCitation Excerpt :A number of other functions including regulation of brain development, modulation of behavioral functions (Willi et al., 2009) and inhibition of neuronal differentiation (Gao et al., 2009) have been attributed to Nogo-A. The inhibitory functions of Nogo-A are mainly related to the extracellular domain Nogo-66, which acts via a receptor complex (Schwab et al., 2006). Neutralization of Nogo-A is a potentially promising therapeutic strategy to enable regeneration of CNS tissue (Zörner and Schwab, 2010).
TROY interacts with Rho guanine nucleotide dissociation inhibitor α (RhoGDIα) to mediate nogo-induced inhibition of neurite outgrowth
2013, Journal of Biological ChemistryCitation Excerpt :The TROY ICD does not harbor the death domain discovered in p75 and some other TNFR family members (e.g. TNFRSF1A, TNFRSF6, and TNFRSF12) (9), although it has been found to be able to induce cell death (10, 11). As the transmembrane component of the NgR trimeric receptor complex, both TROY and p75 were able to mediate MAIF-induced inhibition of axonal regeneration through RhoA activation (7, 12). p75 has been found to facilitate the release of RhoA by competitive binding to the Rho guanine nucleotide dissociation inhibitor α (RhoGDIα) through its mastoparan-like α helix in the death domain (13).
Epidermal growth factor receptor antagonists and CNS axon regeneration: Mechanisms and controversies
2011, Brain Research BulletinCitation Excerpt :For example, blockade of astrocytic pEGFR signalling may attenuate inhibitory scar formation, leading to reduced Rho GTP-mediated signalling of growth cone collapse. Schwab et al. [57] speculated that inter-receptor Ca2+-mediated ‘cross talk’ between the NgR complex and EGFR may trigger a novel signalling cascade through the association with novel adaptor proteins. Notwithstanding the above, our assertion is that EGFR is not the target axis for AG1478/PD168393-mediated axon growth in the optic nerve, but that these EGFR antagonists exert axogenesis through an indirect and off-target mechanism centred on the release of neurotrophins from glia/neurons, which induce RIP of p75NTR/TROY in axon growth cones, paralysing inhibitory ligand signalling through the Rho/ROCK inhibitory pathways, allowing neurotrophins to promote unimpeded axon advance through the inhibitory CNS neuropil.
Effect of the oligodendrocyte myelin glycoprotein (OMgp) on the expansion and neuronal differentiation of rat neural stem cells
2009, Brain ResearchCitation Excerpt :In the other hand, OMgp expressed by oligodendrocytes is known as a myelin inhibitor because it blocks neurite outgrowth on differentiating neurons. This action is mediated in part by activating the Nogo-R1/Rho-A GTPase pathway (Kottis et al., 2002; Vourc'h et al., 2003b; Schwab et al., 2006). We observed that OMgp over-expression by differentiating neurons themselves neither promoted nor inhibited neurite outgrowth.