The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity

Kempf, Anissa; Tews, Bjoern; Arzt, Michael E.; Weinmann, Oliver; Obermair, Franz J.; Pernet, Vincent; Zagrebelsky, Marta; Delekate, Andrea; Iobbi, Cristina; Zemmar, Ajmal; Ristic, Zorica; Gullo, Miriam; Spies, Peter; Dodd, Dana A.; Gygax, Daniel; Körte, Martin; Schwab, Martin E.

doi:10.1371/journal.pbio.1001763

Cited by 154 publications

(175 citation statements)

References 68 publications

(118 reference statements)

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“…39 Targeted Nogo-A ablation promotes axonal outgrowth F Vajda et al Figure S3B). The retinal expressions of NgR1 and S1PR2, a newly identified receptor for Nogo-A, 15 were not modified (Supplementary Figure S5A and Supplementary Figure S3C and F). These data suggest that EphA4 and EphrinA3 upregulation may restrict the distance of axonal regrowth in Cnp-Cre þ / À xRtn4 flox/flox optic nerves following injury.…”

Section: Compensatory Upregulation Of Ephrina3 and Epha4mentioning

confidence: 98%

“…12,13 Neurons express Nogo-A receptors such as the Nogo-66 receptor 1 (NgR1) 14 and the Nogo-A-D20-specific sphingosine 1-phosphate receptor 2 (S1PR2). 15 They can co-express them along with Nogo-A, 13 an observation that raises the possibility of cis-interactions between the ligand and its receptors within or at the cell surface of the same cell. This mechanism has previously been described for axonal guidance molecules such as Ephrins and Semaphorins, and could have a major role in the neuronal response to extracellular growth inhibitors during development.…”

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confidence: 99%

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Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

et al. 2014

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Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre þ / À xRtn4/Nogo-A flox/flox ) and neuron-specific (Thy1-Cre tg þ xRtn4 flox/flox ) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4 flox/flox animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.

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Section: Compensatory Upregulation Of Ephrina3 and Epha4mentioning

confidence: 98%

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confidence: 99%

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

et al. 2014

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“…Upon Nogo-A-binding, NgR1 associates with the transmembrane proteins leucine rich repeat and Immunoglobin-like domain-containing protein 1 (LINGO-1) and p75 or tumour necrosis factor-α (TNFα) receptor superfamily member 19 (TROY) to form a multisubunit receptor complex [49,57]. The sphingosine-1-phosphate receptor 2 (S1PR2) is a receptor for Nogo-A-Δ20 [58] (Fig. 1a).…”

Section: The Nogo-a Protein: Its Distribution and Receptorsmentioning

confidence: 99%

“…Nogo-66 binds to Nogo-receptor 1 (NgR1) which forms a complex with LINGO-1, p75, and/or TROY. Sphingosine-1-phosphate receptor 2 (S1PR2) has recently been identified as a Nogo-A-Δ20 receptor [58].…”

Section: -354 (Human)mentioning

confidence: 99%

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology

et al. 2017

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Two hallmarks of chronic multiple sclerosis lesions are the absence of significant spontaneous remyelination and primary as well as secondary neurodegeneration. Both characteristics may be influenced by the presence of inhibitory factors preventing myelin and neuronal repair. We investigated the potential of antibodies against Nogo-A, a well-known inhibitory protein for neuronal growth and plasticity, to enhance neuronal regeneration and remyelination in two animal models of multiple sclerosis. We induced a targeted experimental autoimmune encephalomyelitis (EAE) lesion in the dorsal funiculus of the cervical spinal cord of adult rats resulting in a large drop of skilled forelimb motor functions. We subsequently observed improved recovery of forelimb function after anti-Nogo-A treatment. Anterograde tracing of the corticospinal tract revealed enhanced axonal sprouting and arborisation within the spinal cord gray matter preferentially targeting pre-motor and motor spinal cord laminae on lesion level and above in the anti-Nogo-A-treated animals. An important additional effect of Nogo-A-neutralization was enhanced remyelination observed after lysolecithin-induced demyelination of spinal tracts. Whereas remyelinated fiber numbers in the lesion site were increased several fold, no effect of Nogo-A-inhibition was observed on oligodendrocyte precursor proliferation, migration, or differentiation. Enhancing remyelination and promoting axonal regeneration and plasticity represent important unmet medical needs in multiple sclerosis. Anti-Nogo-A antibodies hold promise as a potential new therapy for multiple sclerosis, in particular during the chronic phase of the disease when neurodegeneration and remyelination failure determine disability evolution. Key pointsSolid pre-clinical data suggests Nogo-A-neutralization as a potential therapeutic approach for neuroinflammatory and demyelinating pathology. Nogo-A-antibodies are now in early clinical development for multiple sclerosis (MS). Their potential to boost axonal regeneration and compensatory fiber growth as well as myelin repair makes them an attractive candidate to treat also progressive MS in which neurodegeneration and chronic demyelination are hallmarks. AbstractMost of the current therapies as well as many of the clinical trials for Multiple Sclerosis (MS) target the inflammatory autoimmune processes, but less than 20% of all clinical trials investigate potential therapies for the chronic progressive disease stage of MS. The latter is responsible for the steadily increasing disability in many patients, and there is an urgent need for novel therapies that protect nervous system tissue and enhance axonal growth and/or remyelination. As outlined in this review, solid pre-clinical data suggest neutralization of the neurite outgrowth inhibitor Nogo-A as a potential new way to achieve both, axonal and myelin repair. Several phase I clinical studies with anti-Nogo-A antibodies have been conducted in different disease paradigms including MS and spinal cord injur...

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“…These domains interact with different receptor complexes, the downstream signals of which result in the activation of RhoA and Rho kinase (ROCK, for which there are two isoforms ROCK1 and ROCK2), the destabilization of the cytoskeleton and a transcriptiondependent downregulation of the neuronal growth program (Kempf and Schwab, 2013;Schwab, 2010;Schwab and Strittmatter, 2014). Nogo-A-Δ20 elicits the inhibition of neurite outgrowth and fibroblast spreading through the G-protein-coupled receptor sphingosine-1-phosphate receptor 2 (S1PR2) (Kempf et al, 2014). Interestingly, Nogo-A-Δ20 also binds to the membrane protein tetraspanin-3 (TSPAN-3), and the Nogo-A-TSPAN-3 complex then co-clusters with S1PR2.…”

Section: Ephrinsmentioning

confidence: 99%

Attractive and repulsive factors act through multi-subunit receptor complexes to regulate nerve fiber growth

Thiede-Stan

Schwab

2015

Journal of Cell Science

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In the nervous system, attractive and repulsive factors guide neuronal growth, pathfinding and target innervation during development, learning and regeneration after injury. Repulsive and growth-inhibitory factors, such as some ephrins, semaphorins, netrins and myelin-associated growth inhibitors, restrict nerve fiber growth, whereas neurotrophins, and other ephrins, semaphorins and netrins attract fibers and promote neurite growth. Several of these guidance molecules also play crucial roles in vasculogenesis, and regulate cell migration and tissue formation in different organs. Precise and highly specific signal transduction in space and time is required in all these cases, which primarily depends on the presence and function of specific receptors. Interestingly, many of these ligands act through multi-subunit receptor complexes. In this Commentary, we review the current knowledge of how complexes of the receptors for attractive and repulsive neurite growth regulatory factors are reorganized in a spatial and temporal manner, and reveal the implications that such dynamics have on the signaling events that coordinate neurite fiber growth.

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The Sphingolipid Receptor S1PR2 Is a Receptor for Nogo-A Repressing Synaptic Plasticity

Abstract: This study identifies a GPCR, S1PR2, as a receptor for the Nogo-A-Δ20 domain of the membrane protein Nogo-A, which inhibits neuronal growth and synaptic plasticity.

Cited by 154 publications

References 68 publications

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

Nogo-A antibodies enhance axonal repair and remyelination in neuro-inflammatory and demyelinating pathology

Attractive and repulsive factors act through multi-subunit receptor complexes to regulate nerve fiber growth

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