Myelin-Associated Glycoprotein Interacts with the Nogo66 Receptor to Inhibit Neurite Outgrowth

Abstract

Myelin inhibitors of axonal regeneration, like Nogo and MAG, block regrowth after injury to the adult CNS. While a GPI-linked receptor for Nogo (NgR) has been identified, MAG's receptor is unknown. We show that MAG inhibits regeneration by interaction with NgR. Binding of and inhibition by MAG are lost if neuronal GPI-linked proteins are cleaved. Binding of MAG to NgR-expressing cells is GPI dependent and sialic acid independent. Conversely, NgR binds to MAG-expressing cells. MAG, but not a truncated MAG that binds neurons but does not inhibit regeneration, precipitates NgR from NgR-expressing cells, DRG, and cerebellar neurons. Importantly, NgR antibody, soluble NgR, or dominant-negative NgR each prevent inhibition of neurite outgrowth by MAG. Also, MAG and Nogo66 compete for binding to NgR. These results suggest redundancy in myelin inhibitors and indicate therapies for CNS injuries.

Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS

“…They conclude, therefore, that Nogo-66 is the main inhibitor, because when only Nogo-66 is blocked does considerable regeneration occur. By contrast, we showed that Mag could compete with Nogo-66 for binding to Ngr 36 .…”

“…library, and they found a new ligand that was shown to be Mag 35 . At the same time, our group had co-precipitated the two proteins and had also identified Ngr as a receptor for Mag 36 . Together, these two studies provided compelling evidence that Ngr is required for Mag to exert its inhibition.…”

“…Given that Nogo-66, Mag and Omgp all interact with Ngr with about the same relatively high affinity 28,32,35,36 , and assuming that they are the only inhibitors (but see later discussion on amino-Nogo) and that there is only one receptor complex, the contribution that each makes depends on two factors -their relative abundance in myelin, and the likelihood of a growth cone encountering each inhibitor as it attempts to regenerate. Mag represents 1 % and 0.1 % of the total myelin protein in the CNS and PNS, respectively, and it is found mostly in the inner myelin loop in the CNS 23,49 .…”

Selective temporal and regional alterations of Nogo-A and small proline-rich repeat protein 1A (SPRR1A) but not Nogo-66 receptor (NgR) occur following traumatic brain injury in the rat

“…Nogo-66, together with both MAG and OMgp, bind and activate the same receptor, the neuronal, glycosyl-phosphatidyl-inositol (GPI)-anchored Nogo-66 Receptor (NgR; Fournier et al, 2001;Domeniconi et al, 2002;Liu et al, 2002a;Wang et al, 2002a) with additional molecules including p75 NTR , Lingo-1 and TAJ/TROY required for signaling (Mi et al, 2004;Shao et al, 2005;Park et al, 2005).…”

Setting the stage for functional repair of spinal cord injuries: a cast of thousands

“…[47][48][49][50] As an apparent point of convergence in inhibitory signaling, NgR has taken the stage as a target of strategies aimed at increasing plasticity in the injured spinal cord. A competitive antagonist of NgR, NEP1-40, blocks the inhibitory action of myelin in vitro 51 and enhances both growth of supraspinal axons and functional recovery when administered intrathecally or systemically after thoracic hemisection.…”