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: 16.1). 03/2012; 15(5):703-12. DOI: 10.1038/nn.3070
Source: PubMed


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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    • " poor substrate and electrostatically repel growth cones . Protein tyrosine phosphatase sigma ( PTPsigma ) , leukocyte common antigen related phosphatase ( LAR ) and NgR have been identified as neuronal receptors that functionally interact with and mediate CSPG - dependent inhibition of neuron growth ( Shen et al . , 2009 ; Fisher et al . , 2011 ; Dickendesher et al . , 2012 ) . Chondroitinase ABC ( chABC ) , a bacterial enzyme that digests the GAG chains , abrogates CSPG - dependent neurite outgrowth inhibition in vitro and improves neurite sprouting and functional recovery after SCI ( Bradbury et al . , 2002 ) . The efficacy of chABC alone and in combination with other approaches in promoting recovery aft"
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    • "The low-power micrographs presented in Figure 1 show the extent of this growth in pre-injured CAST/Ei neurons, a finding that was replicated multiple times (see Experimental Procedures). The sensory neurons from the CAST/Ei mice also exhibited elevated levels of growth compared to those from C57BL/6 mice when grown on chondroitin sulfate proteoglycans (CSPGs), an inhibitory substrate found in glial scars (Dickendesher et al., 2012; Fisher et al., 2011; Shen et al., 2009). Pre-conditioned CAST/Ei neurons grew far more robustly than pre-conditioned C57BL/6 neurons on both CSPGs (4-fold increase, p < 0.05, 56.7 [17.0]; "
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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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