The Nogo receptor complex: confining molecules to molecular mechanisms

doi:10.1016/j.molmed.2006.05.001

Trends in Molecular Medicine

Volume 12, Issue 7, July 2006, Pages 293-297

https://doi.org/10.1016/j.molmed.2006.05.001 Get rights and content

Myelin inhibitory ligands of the Nogo-66 receptor (NgR1) limit axon regeneration in the adult CNS. Recent findings have identified additional co-receptors (functional homologues) of the trimeric NgR1 complex, post-translational modifications of the co-receptors within the cell membrane and novel Ca²⁺-dependent cytoplasmic-protein phosphorylation mechanisms. Such unique signalling pathways provide the potential to transduce myelin-derived growth inhibitory signals to the axonal cytoskeleton, and have been areas of intense investigation in recent years. Here, we summarize current understanding of the molecular basis of myelin-derived axon-growth inhibition in the CNS.

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-A^544–725 domain (also known as Amino-Nogo-A), which is

New members of the trimeric NgR1 complex: p75^NTR, 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 (p75^NTR)-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: p75^NTR cleavage by secretases

A new mechanism of NgR1-mediated intra-neuronal signal integration has been unravelled by modifying one of the transducing components, p75^NTR (Figure 1b). Upon stimulation with MAG, the NgR1 complex triggers intramembrane proteolysis (RIP) of the co-receptor p75 [21]. p75^NTR is sequentially cleaved by α-secretase and γ-secretase in a protein-kinase-C (PKC)-dependent manner. The cleaved cytoplasmic product of p75^NTR – 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).

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Cited by (30)

A decade from discovery to therapy: Lingo-1, the dark horse in neurological and psychiatric disorders
2015, Neuroscience and Biobehavioral Reviews
Citation 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.
Leucine-rich repeat and immunoglobulin domain-containing protein (Lingo-1) is a potent negative regulator of neuron and oligodendrocyte survival, neurite extension, axon regeneration, oligodendrocyte differentiation, axonal myelination and functional recovery; all processes highly implicated in numerous brain-related functions. Although playing a major role in developmental brain functions, the potential application of Lingo-1 as a therapeutic target for the treatment of neurological disorders has so far been under-estimated. A number of preclinical studies have shown that various methods of antagonizing Lingo-1 results in neuronal and oligodendroglial survival, axonal growth and remyelination; however to date literature has only detailed applications of Lingo-1 targeted therapeutics with a focus primarily on myelination disorders such as multiple sclerosis and spinal cord injury; omitting important information regarding Lingo-1 signaling co-factors. Here, we provide for the first time a complete and thorough review of the implications of Lingo-1 signaling in a wide range of neurological and psychiatric disorders, and critically examine its potential as a novel therapeutic target for these disorders.
Non-canonical actions of Nogo-A and its receptors
2015, Biochemical Pharmacology
Nogo-A is a myelin associated protein and one of the most potent neurite growth inhibitors in the central nervous system. Interference with Nogo-A signaling has thus been investigated as therapeutic target to promote functional recovery in CNS injuries. Still, the finding that Nogo-A presents a fairly ubiquitous expression in many types of neurons in different brain regions, in the eye and even in the inner ear suggests for further functions besides the neurite growth repression. Indeed, a growing number of studies identified a variety of functions including regulation of neuronal stem cells, modulation of microglial activity, inhibition of angiogenesis and interference with memory formation. Aim of the present commentary is to draw attention on these less well-known and sometimes controversial roles of Nogo-A. Furthermore, we are addressing the role of Nogo-A in neuropathological conditions such as ischemic stroke, schizophrenia and neurodegenerative diseases.
Loss of Nogo-A-expressing neurons in a rat model of Parkinson's disease
2015, Neuroscience
Citation 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).
The myelin-associated protein Nogo-A is among the most potent neurite growth inhibitors in the adult CNS. Recently, Nogo-A expression was demonstrated in a number of neuronal subpopulations of the adult and developing CNS but at present, little is known about the expression of Nogo-A in the nigrostriatal system, a brain structure severely affected in Parkinson’s disease (PD). The present study sought to characterize the expression pattern of Nogo-A immunoreactive (ir) cells in the adult ventral mesencephalon of control rats and in the 6-hydroxydopamine (6-OHDA) rat model of PD. Immunohistochemical analyses of normal adult rat brain showed a distinct expression of Nogo-A in the ventral mesencephalon, with the highest level in the substantia nigra pars compacta (SNc) where it co-localized with dopaminergic neurons. Analyses conducted 1 week and 1 month after unilateral striatal injections of 6-OHDA disclosed a severe loss of the number of Nogo-A-ir cells in the SNc. Notably, at 1 week after treatment, more dopaminergic neurons expressing Nogo-A were affected by the 6-OHDA toxicity than Nogo-A-negative dopaminergic neurons. However, at later time points more of the surviving dopaminergic neurons expressed Nogo-A. In the striatum, both small and large Nogo-A-positive cells were detected. The large cells were identified as cholinergic interneurons. Our results suggest yet unidentified functions of Nogo-A in the CNS beyond the inhibition of axonal regeneration and plasticity, and may indicate a role for Nogo-A in PD.
TROY interacts with Rho guanine nucleotide dissociation inhibitor α (RhoGDIα) to mediate nogo-induced inhibition of neurite outgrowth
2013, Journal of Biological Chemistry
Citation 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).
TROY can functionally substitute p75 to comprise the Nogo receptor complex, which transduces the inhibitory signal of myelin-associated inhibitory factors on axon regeneration following CNS injury. The inhibition of neurite extension relies on TROY-dependent RhoA activation, but how TROY activates RhoA remains unclear. Here, we firstly identified Rho guanine nucleotide dissociation inhibitor α (RhoGDIα) as a binding partner of TROY using GST pull-down combined with two-dimensional gel electrophoresis and mass spectra analysis. The interaction was further confirmed by coimmunoprecipitation in vitro and in vivo. Deletion mutagenesis revealed that two regions of the TROY intracellular domain (amino acids 234–256 and 321–350) were essential for the interaction with RhoGDIα. Secondly, TROY and RhoGDIα were coexpressed in postnatal dorsal root ganglion neurons, cortex neurons, and cerebellar granule neurons (CGNs). Thirdly, TROY/RhoGDIα association was potentiated by Nogo-66 and was independent of p75/RhoGDIα interaction. Fourthly, TROY/RhoGDIα interaction was still able to activate RhoA when p75 was deficient. Furthermore, RhoA activation was decreased dramatically when TROY was knocked down in p75-deficient CGNs cells. Finally, RhoGDIα overexpression abolished RhoA activation and following neurite outgrowth inhibition by Nogo-66 in both wild-type and p75-deficient CGNs. These results showed that the association of RhoGDIα with TROY contributed to TROY-dependent RhoA activation and neurite outgrowth inhibition after Nogo-66 stimulation.
Epidermal growth factor receptor antagonists and CNS axon regeneration: Mechanisms and controversies
2011, Brain Research Bulletin
Citation 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.
The reasons for the failure of central nervous system (CNS) axons to regenerate include the presence of myelin- and non-myelin derived inhibitory molecules, neuronal apoptosis and the absence of a potent neurotrophic stimulus. Transactivation of the epidermal growth factor receptor (EGFR) has been implicated in signalling inhibition of axon growth in the CNS. Small molecule EGFR inhibitors such as AG1478 and PD168393 promote CNS axon growth after optic nerve transection despite the presence of inhibitory molecules in the environment of the regenerating axon. However, our results demonstrate that phosphorylated EGFR (pEGFR) is not present on regenerating axons and that the majority of pEGFR is present in glia, suggesting that EGFR cannot play a direct intra-axonal role in signalling inhibition and thus disinhibited CNS axon growth must be indirectly mediated by glia. We argue that EGFR may not have a role in signalling axon growth inhibition since AG1478 and PD168393 promotes neuronal neurite outgrowth in CNS myelin-inhibited cultures after EGFR knockdown. This review discusses the current evidences for and against the involvement of EGFR in signalling myelin inhibition.
Effect of the oligodendrocyte myelin glycoprotein (OMgp) on the expansion and neuronal differentiation of rat neural stem cells
2009, Brain Research
Citation 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.
The oligodendrocyte myelin glycoprotein (OMgp) inhibits axon regeneration after injury in the adult mammalian central nervous system. However its function during brain development remains largely unknown. The present study aims to analyze a possible role for OMgp during neurogenesis. We showed that neural stem cells (NSC) extracted from the whole mesencephalon of rat embryos (E14) and cultured as free floating neurospheres expressed both OMgp and its receptor Nogo-R1. An over-expression of OMgp affected NSC expansion by reducing cell proliferation, but did not affect their differentiation into neurons. These findings indicate a new role for OMgp during brain development as a possible regulator of neurogenesis. Moreover, they suggest a possible implication for OMG gene in the etiology of neurofibromatosis type 1 forms characterized by a deletion of the NF1 gene locus containing OMG.

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Trends in Molecular Medicine

Research FocusThe Nogo receptor complex: confining molecules to molecular mechanisms

Section snippets

Myelin inhibition of axonal regeneration: Nogo-A

New members of the trimeric NgR1 complex: p75NTR, LINGO-1 and TROY/TAJ

Intramembrane proteolysis: p75NTR cleavage by secretases

Epidermal growth factor receptor: an unexpected candidate of axoplasmic second-messenger systems

Concluding remarks

Acknowledgements

Oligodendrocytes and CNS myelin are nonpermissive substrates for neurite growth and fibroblast spreading in vitro

J. Neurosci.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

Nat. Rev. Neurosci.

Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions

J. Neurosci.

Identification of a receptor mediating Nogo-66 inhibition of axonal regeneration

Nature

Structure and axon outgrowth inhibitor binding of the Nogo-66 receptor and related proteins

EMBO J.

The Nogo-66 receptor homolog NgR2 is a sialic acid-dependent receptor selective for myelin-associated glycoprotein

J. Neurosci.

Nogo-A, -B, and -C are found on the cell surface and interact together in many different cell types

J. Biol. Chem.

Nogo-A interacts with the Nogo-66 receptor through multiple sites to create an isoform-selective subnanomolar agonist

J. Neurosci.

Targeting the Nogo receptor to treat central nervous system injuries

Nat. Rev. Drug Discov.

The transmembrane semaphorin Sema4D/CD100, an inhibitor of axonal growth, is expressed on oligodendrocytes and upregulated after CNS lesion

J. Neurosci.

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

Research Focus
The Nogo receptor complex: confining molecules to molecular mechanisms

New members of the trimeric NgR1 complex: p75^NTR, LINGO-1 and TROY/TAJ

Intramembrane proteolysis: p75^NTR cleavage by secretases