Wong, S.T. et al. A p75(NTR) and Nogo receptor complex mediates repulsive signaling by myelin-associated glycoprotein. Nat. Neurosci. 5, 1302-1308

Division of Neurobiology, Department of Molecular and Cell Biology, University of California, Berkeley, California 94720, USA.
Nature Neuroscience (Impact Factor: 16.1). 01/2003; 5(12):1302-8. DOI: 10.1038/nn975
Source: PubMed


Myelin-associated glycoprotein (MAG), an inhibitor of axon regeneration, binds with high affinity to the Nogo-66 receptor (NgR). Here we report that the p75 neurotrophin receptor (p75(NTR)) is a co-receptor of NgR for MAG signaling. In cultured human embryonic kidney (HEK) cells expressing NgR, p75(NTR) was required for MAG-induced intracellular Ca2+ elevation. Co-immunoprecipitation showed an association of NgR with p75(NTR) that can be disrupted by an antibody against p75(NTR) (NGFR5), and extensive coexpression was observed in the developing rat nervous system. Furthermore, NGFR5 abolished MAG-induced repulsive turning of Xenopus axonal growth cones and Ca2+ elevation, both in neurons and in NgR/p75(NTR)-expressing HEK cells. Thus we conclude that p75(NTR) is a co-receptor of NgR for MAG signaling and a potential therapeutic target for promoting nerve regeneration.

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    • "Pro-neurotrophins engage p75 NTR together with members of the Vps10 family, including sortilin, SorL1 and SorCS2 (Nykjaer and Willnow, 2012; Nykjaer et al., 2004). Myelin-derived ligands require expression of Nogo receptor (NgR, also known as RTN4R) and Lingo-1 for signaling through p75 NTR (Mi et al., 2004; Wang et al., 2002; Wong et al., 2002). p75 NTR is known to engage different signaling pathways in the cell, of which the three most important ones are the JNK or caspase pathway, which mediates cell death (Friedman, 2000; Yoon et al., 1998), the RhoA pathway, which regulates axon growth, collapse and degeneration (Park et al., 2010; Yamashita and Tohyama, 2003; Yamashita et al., 1999) and the NF-kB pathway, which has been implicated in cell survival (Carter et al., 1996; Khursigara et al., 2001). "
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    ABSTRACT: Signaling by the p75 neurotrophin receptor (p75(NTR)) is often referred to as cell-context dependent, but neuron-type specific signaling by p75(NTR) has not been systematically investigated. Here, we report that p75(NTR) signals very differently in hippocampal neurons (HCNs) and cerebellar granule neurons (CGNs), and present evidence indicating that this is partly controlled by differential proteolytic cleavage. NGF induced caspase-3 activity and cell death in HCNs but not in CGNs, while it stimulated NFκB activity in CGNs but not in HCNs. HCNs and CGNs displayed different patterns of p75(NTR) proteolytic cleavage. While the p75(NTR) carboxy terminal fragment (CTF) was more abundant than the intracellular domain (ICD) in HCNs, CGNs exhibited fully processed ICD with very little CTF. Pharmacological or genetic blockade of p75(NTR) cleavage by gamma-secretase abolished NGF-induced upregulation of NFκB activity and enabled induction of CGN death, phenocopying the functional profile of HCNs. Thus, the activities of multifunctional receptors, such as p75(NTR), can be tuned into narrower activity profiles by cell-type-specific differences in intracellular processes, such as proteolytic cleavage, leading to very different biological outcomes.
    Journal of Cell Science 02/2015; 128(8). DOI:10.1242/jcs.161745 · 5.43 Impact Factor
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    • "The adult mammalian central nervous system (CNS) cannot be repaired spontaneously after injury. The lack of regenerative capacity in the mammalian CNS is partly due to the myelin-associated proteins including Nogo-A1, myelin-associated glycoprotein23 and oligodendrocyte myelin glycoprotein45. Nogo-66 receptor 1 (NgR1) is a common receptor for the myelin-associated inhibitors of the regeneration (i.e., Nogo-A, myelin-associated glycoprotein and oligodendrocyte myelin glycoprotein)6, as well as chondroitin sulphate proteoglycans7. Inhibition of NgR activation with neutralising antibodies against Nogo-A8, a peptide mimicking NgR1-binding region of Nogo-A (NEP1-40)9 or the ecto-domain part of NgR1 (NgR1(310) ecto-Fc)10, can promote functional recovery of the spinal cord after traumatic injury. "
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    ABSTRACT: Inhibition of Nogo-66 receptor (NgR) can promote recovery following spinal cord injury. The ecto-domain of NgR can be phosphorylated by protein kinase A (PKA), which blocks activation of the receptor. Here, we found that infusion of PKA plus ATP into the damaged spinal cord can promote recovery of locomotor function. While significant elongation of cortical-spinal axons was not detectable even in the rats showing enhanced recovery, neuronal precursor cells were observed in the region where PKA plus ATP were directly applied. NgR1 was expressed in neural stem/progenitor cells (NSPs) derived from the adult spinal cord. Both an NgR1 antagonist NEP1-40 and ecto-domain phosphorylation of NgR1 promote neuronal cell production of the NSPs, in vitro. Thus, inhibition of NgR1 in NSPs can promote neuronal cell production, which could contribute to the enhanced recovery of locomotor function following infusion of PKA and ATP.
    Scientific Reports 05/2014; 4:4972. DOI:10.1038/srep04972 · 5.58 Impact Factor
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    • "Nogo-66 is a 66 amino acid domain that, together with flanking hydrophobic regions, is a component of the RTN homology domain in the C-terminus of all Nogo isoforms [6]. Nogo-66 collapse-inducing activity is associated with high-affinity binding to its receptors NgR1 [7], [8], which forms a complex with the transmembrane proteins LINGO1, and p75 or TROY [1], [9]–[11]. Nogo-66 can also bind to the paired immunoglobulin-like receptor PirB [11]. "
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    ABSTRACT: The protein Nogo-A regulates axon growth in the developing and mature nervous system, and this is carried out by two distinct domains in the protein, Nogo-A-Δ20 and Nogo-66. The differences in the signalling pathways engaged in axon growth cones by these domains are not well characterized, and have been investigated in this study. We analyzed growth cone collapse induced by the Nogo-A domains Nogo-A-Δ20 and Nogo-66 using explanted chick dorsal root ganglion neurons growing on laminin/poly-lysine substratum. Collapse induced by purified Nogo-A-Δ20 peptide is dependent on protein synthesis whereas that induced by Nogo-66 peptide is not. Nogo-A-Δ20-induced collapse is accompanied by a protein synthesis-dependent rise in RhoA expression in the growth cone, but is unaffected by proteasomal catalytic site inhibition. Conversely Nogo-66-induced collapse is inhibited ∼50% by proteasomal catalytic site inhibition. Growth cone collapse induced by the Nogo-A domains Nogo-A-Δ20 and Nogo-66 is mediated by signalling pathways with distinguishable characteristics concerning their dependence on protein synthesis and proteasomal function.
    PLoS ONE 01/2014; 9(1):e86820. DOI:10.1371/journal.pone.0086820 · 3.23 Impact Factor
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