Article

NgR1 and NgR3 are Receptors for Chondroitin Sulfate Proteoglycans

Neuroscience Program, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.
Nature Neuroscience (Impact Factor: 14.98). 03/2012; 15(5):703-12. DOI: 10.1038/nn.3070
Source: PubMed

ABSTRACT In the adult mammalian CNS, chondroitin sulfate proteoglycans (CSPGs) and myelin-associated inhibitors (MAIs) stabilize neuronal structure and restrict compensatory sprouting following injury. The Nogo receptor family members NgR1 and NgR2 bind to MAIs and have been implicated in neuronal inhibition. We found that NgR1 and NgR3 bind with high affinity to the glycosaminoglycan moiety of proteoglycans and participate in CSPG inhibition in cultured neurons. Nogo receptor triple mutants (Ngr1(-/-); Ngr2(-/-); Ngr3(-/-); which are also known as Rtn4r, Rtn4rl2 and Rtn4rl1, respectively), but not single mutants, showed enhanced axonal regeneration following retro-orbital optic nerve crush injury. The combined loss of Ngr1 and Ngr3 (Ngr1(-/-); Ngr3(-/-)), but not Ngr1 and Ngr2 (Ngr1(-/-); Ngr2(-/-)), was sufficient to mimic the triple mutant regeneration phenotype. Regeneration in Ngr1(-/-); Ngr3(-/-) mice was further enhanced by simultaneous ablation of Rptpσ (also known as Ptprs), a known CSPG receptor. Collectively, our results identify NgR1 and NgR3 as CSPG receptors, suggest that there is functional redundancy among CSPG receptors, and provide evidence for shared mechanisms of MAI and CSPG inhibition.

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Available from: Roman J Giger, Aug 04, 2015
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    • "Importantly, manipulation of these receptors provides new therapeutic targets for overcoming CSPGs inhibitory properties following CNS injury. Emerging evidence is currently shedding light on the potential benefits of inhibiting these receptors for axonal regeneration (Coles et al., 2011; Dickendesher et al., 2012; Fisher et al., 2011; Fry et al., 2010; Lang et al., 2015). Moreover, inhibition of these receptors in combination with other therapeutic strategies may maximize therapeutic benefits of their inhibition for improving a meaningful functional recovery following SCI. "
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    ABSTRACT: Chondroitin Sulfate Proteoglycans (CSPGs) are a major component of the extracellular matrix in the central nervous system (CNS) and play critical role in the development and pathophysiology of the brain and spinal cord. Developmentally, CSPGs provide guidance cues for growth cones and contribute to the formation of neuronal boundaries in the developing CNS. Their presence in perineuronal nets plays a crucial role in the maturation of synapses and closure of critical periods by limiting synaptic plasticity. Following injury to the CNS, CSPGs are dramatically upregulated by reactive glia which form a glial scar around the lesion site. Increased level of CSPGs is a hallmark of all CNS injuries and has been shown to limit axonal plasticity, regeneration, remyelination, and conduction after injury. Additionally, CSPGs create a non-permissive milieu for cell replacement activities by limiting cell migration, survival and differentiation. Mounting evidence is currently shedding light on the potential benefits of manipulating CSPGs in combination with other therapeutic strategies to promote spinal cord repair and regeneration. Moreover, the recent discovery of multiple receptors for CSPGs provides new therapeutic targets for targeted interventions in blocking the inhibitory properties of CSPGs following injury. Here, we will provide an in depth discussion on the impact of CSPGs in normal and pathological CNS. We will also review the recent preclinical therapies that have been developed to target CSPGs in the injured CNS. Copyright © 2015. Published by Elsevier Inc.
    Experimental Neurology 04/2015; 269. DOI:10.1016/j.expneurol.2015.04.006
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    • "NSCs treated with the PTPσ receptor ecto compared to the control group (Dickendesher et al. 2012; Ramasamy et al. 2014; Shen et al. 2009 "
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    ABSTRACT: Neural stem cells (NSCs) could produce various cell phenotypes in the subventricular zone (SVZ) and dentate gyrus of the hippocampus in the central nervous system (CNS), where neurogenesis has been determined to occur. The extracellular microenvironment also influences the behaviors of NSCs during development and at CNS injury sites. Our previous study indicates that myelin, a component of the CNS, could regulate the differentiation of NSCs in vitro. Recent reports have implicated three myelin-derived inhibitors, NogoA, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp), as well as several axon guidance molecules as regulators of NSC survival, proliferation, migration, and differentiation. However, the molecular mechanisms underlying the behavior of NSCs are not fully understood. In this study, we summarize the current literature on the effects of different extrinsic factors on NSCs and discuss possible mechanisms, as well as future possible clinical applications.
    Journal of Molecular Neuroscience 03/2015; DOI:10.1007/s12031-015-0538-1
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    • "In addition, paired immunoglobulin-like receptor B (PirB) was identified as an additional highaffinity receptor for Nogo, MAG and OMgp (Atwal et al., 2008). Although MAIs have important roles in stabilizing intricate neuronal networks in the uninjured CNS, their capacity for restricting axonal sprouting, regeneration and plasticity may impair clinical recovery after TBI (Akbik et al., 2012; Dickendesher et al., 2012; Kempf and Schwab, 2013; Raiker et al., 2010). Antibodies inhibiting Nogo-A, MAG or NgR1 consistently resulted in improved outcome when used following stroke or spinal cord injury (SCI) (Fang et al., 2010; Gillani et al., 2010; Omoto et al., 2010; Tsai et al., 2011; Papadopoulos et al., 2002; Lee et al., 2004; Irving et al., 2005; Markus et al., 2005). "
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    ABSTRACT: Purpose: When central nervous system axons are injured, regeneration is partly inhibited by myelin-associated inhibitors (MAIs). Following traumatic brain injury (TBI) in the rat, pharmacological neutralisation of the MAIs Nogo-A and myelin-associated glycoprotein (MAG) resulted in improved functional outcome. In contrast, genetic or pharmacological neutralization of the MAI receptors Nogo-66 receptor 1 (NgR1) or paired-immunoglobulin like receptor-B (PirB) showed an unaltered or impaired outcome following TBI in the mouse. The aim of the present study was thus to evaluate the MAI expression levels following TBI in mice. Methods: Quantitative reverse transcriptase PCR (qRT-PCR) was used to measure total RNA isolated from brains of young adult male C57BL/6 mice at one, three or seven days following controlled cortical impact TBI or sham injury. Hippocampal and neocortical tissue ipsi- and contralateral to the injury was analyzed for Nogo-A, oligodendrocyte-myelin glycoprotein (OMgp), MAG, and the MAI receptors PirB and NgR1, including its co-receptor Lingo1. Results: Compared to sham-injured controls, PirB neocortical expression was significantly upregulated at one day and NgR1 expression downregulated at seven days post-TBI. In the hippocampus, transcriptional upregulation was observed in Nogo-A (one day), MAG and PirB at seven days post-injury. In contrast, the hippocampal transcripts of NgR1 and Lingo1 were decreased at seven days post-injury. The expression of OMgp was unaltered at all time points post-injury. Conclusion: These results suggest that early dynamic changes in MAI gene expression occur following TBI in the mouse, particularly in the hippocampus, which may play an inhibitory role for post-injury regeneration and plasticity.
    Restorative neurology and neuroscience 07/2014; 32(5). DOI:10.3233/RNN-140419
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