NgR-p75(NTR)-Mediated Signaling
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NgR-p75(NTR)-Mediated Signaling
Axon regeneration is arrested in the injured CNS (Central Nervous System) by axon growth-inhibitory ligands expressed in oligodendrocytes/myelin and reactive astrocytes in the lesion and by fibroblasts in scar tissue. Growth cone receptors bind inhibitory ligands, activating a Rho-family GTPase intracellular signaling pathway that disrupts the actin cytoskeleton inducing growth cone collapse/repulsion. The known inhibitory ligands include Eph (Ephrins) expressed on astrocyte/fibroblast membranes; the myelin/oligodendrocyte-derived growth inhibitors Nogo, MAG(Myelin-Associated Glycoprotein), and OMGP (Oligodendrocyte Myelin Glycoprotein); and membrane-bound Sema (Semaphorins) produced by meningeal fibroblasts invading the scar (Ref.1).

The ligand-binding receptor for all the myelin inhibitors is NgR (Nogo Receptor) and requires p75(NTR) (p75 Neurotrophin Receptor) for transmembrane signaling. NgR is a GPI (Glycosyl Phosphatidylinositol)-linked LRR (Leucine-Rich Repeat) protein expressed in multiple types of neurons. p75(NTR) interacts with NgR to form a receptor complex that mediates signaling by Nogo66, MAG, and OMGP. The Rho family of small GTPases (Guanosine Triphosphatases) which includes CDC42, Rac1, PAK (p21-Activated Kinase) and RhoA play an important role in transducing extracellular signals to changes in cytoskeletal proteins. CDC42 and Rac1 mediate growth cone attraction and neurite growth, whereas RhoA causes growth cone repulsion and collapse. These Rho GTPases cycle between the GTP-bound active and GDP (Guanosine Diphosphate)-bound inactive forms. The cycling of these GTPases between active and inactive states is regulated by GEFs (Guanine Nucleotide Exchange Factors) that promote GDP release and GAPs (GTPase-Activating Proteins) that promote GTP hydrolysis (Ref.2). Active GTP-bound RhoA binds to multiple effectors like ROCK (Rho Kinase), MLCK (Myosin Light Chain Kinase) and MLC (Myosin Light Chain) that transduce Rho signals to the actin cytoskeleton.

Nogo is expressed in three distinct isoforms, NogoA, NogoB, and NogoC. Among these, NogoA is the only one that is expressed in oligodendrocytes and consists of two inhibitory domains: a unique amino-terminal region and a 66 amino acid loop termed Nogo66 that is common to all three isoforms. NgR that binds to Nogo66 also serves as a high-affinity receptor for MAG. MAG is a member of the immunoglobulin superfamily and contains five Ig-like domains. It has both adhesive and inhibitory properties and is exclusively found in the myelin sheaths of both oligodendrocytes and Schwann cells. MAG binds to the same LRR domain of NgR as does Nogo66 but to a separate binding site. As a result, MAG and Nogo66 have additive effects on neurite growth inhibition. MAG binds to neurons via a sialic acid linkage involving the gangliosides GT1b and GDAP1 (GD1a), a subclass of glycosphingolipids containing one or more sialic acid residues (Ref.1). Neurite growth inhibition by MAG is induced by growth cone collapse and this collapsing activity is specific for axonal but not dendritic growth cones. Interaction of MAG or myelin with the neuron also activate a GN-AlphaI protein, which is not in the direct signaling pathway for inhibition but inhibits adenylate cyclase by NTF (Neurotrophin)-TRK (Tyrosine Kinase Receptors) dependent increases in cAMP (cyclic Adenosine 3, 5’-Monophosphate) (Ref.5). High cAMP levels in developing neurons override the growth inhibitory response to MAG. cAMP activates PKA (Protein Kinase-A), which affect inhibition directly, probably by inactivating Rho and also by triggering transcription of genes such as Arg1 (Arginase-1), resulting in an increase in synthesis of polyamines. Overexpression of Arg1 or exogenous polyamines can overcome inhibition by MAG and myelin (Ref.3, 4, 6 & 7). Like NogoA and MAG, OMGP is localized at the cell surface and in myelin. It is a GPI-anchored protein and is highly expressed in mature oligodendrocytes. OMGP also inhibits neurite growth from hippocampal neurons and induces growth cone collapse.

The physiological functions of Nogo, MAG, and OMGP likely extend beyond axon outgrowth inhibition. There is also some indication that these proteins may function to limit plasticity and prevent the formation of aberrant connections in the intact adult CNS. Nogo and NgR are expressed during synaptogenesis and NgR expression is consistent with a specific role in receiving Nogo signals. Nogo may have additional roles unrelated to NgR in early development of multiple tissues, including brain and skeletal muscle. OMGP is also be involved in the formation and maintenance of myelin sheaths.