MAG and OMgp Synergize with Nogo-A to Restrict Axonal Growth and Neurological Recovery after Spinal Cord Trauma

Abstract

Functional recovery after adult CNS damage is limited in part by myelin inhibitors of axonal regrowth. Three molecules, Nogo-A, MAG, and OMgp, are produced by oligodendrocytes and share neuronal receptor mechanisms through NgR1 and PirB. While each has an axon-inhibitory role in vitro, their in vivo interactions and relative potencies have not been defined. Here, we compared mice singly, doubly, or triply mutant for these three myelin inhibitor proteins. The myelin extracted from Nogo-A mutant mice is less inhibitory for axons than is that from wild-type mice, but myelin lacking MAG and OMgp is indistinguishable from control. However, myelin lacking all three inhibitors is less inhibitory than Nogo-A-deficient myelin, uncovering a redundant and synergistic role for all three proteins in axonal growth inhibition. Spinal cord injury studies revealed an identical in vivo hierarchy of these three myelin proteins. Loss of Nogo-A allows corticospinal and raphespinal axon growth above and below the injury, as well as greater behavioral recovery than in wild-type or heterozygous mutant mice. In contrast, deletion of MAG and OMgp stimulates neither axonal growth nor enhanced locomotion. The triple-mutant mice exhibit greater axonal growth and improved locomotion, consistent with a principal role for Nogo-A and synergistic actions for MAG and OMgp, presumably through shared receptors. These data support the hypothesis that targeting all three myelin ligands, as with NgR1 decoy receptor, provides the optimal chance for overcoming myelin inhibition and improving neurological function.

Myelin-derived ephrinB3 restricts axonal regeneration and recovery after adult CNS injury

“…S2). These results confirm the previous findings for the two biochemically distinct myelin fractions (21,30) and suggest that ephrinB3 may contribute to myelin inhibition in vivo.…”

“…Dialyzed CHAPS-soluble myelin extract from NMO −/− mice is less inhibitory than that of ephrinB3 +/+ and ephrinB3 −/− myelin (494 ± 22 μm versus 217 ± 44 μm and 205 ± 57 μm per neuron, respectively; Fig. S2), consistent with previous studies (21,30). However, the CHAPS-insoluble extract from myelin of ephrinB3 −/− mice is significantly less inhibitory than that from ephrinB3 +/+ or NMO −/− mice (522 ± 15 μm versus 442 ± 13 μm and 426 ± 45 μm per neuron, respectively; P < 0.01, ANOVA; Fig.…”

“…These findings confirm a previous study undertaken by Benson and colleagues that showed that ephrinB3 is a potent inhibitor of neurite outgrowth (21). Whereas inhibition by the detergent-resistant fraction depends largely on ephrinB3 for inhibition, the detergent-soluble fraction of myelin depends primarily on the combination of Nogo, MAG, and OMgp (30). Spinal cord injury studies with ephrinB3 −/− mice here, in combination with previous studies with Nogo, MAG, OMgp triple knockout mice (30), suggest that all four proteins contribute to in vivo limitation of axonal growth after CNS trauma by myelin.…”

“…Whereas inhibition by the detergent-resistant fraction depends largely on ephrinB3 for inhibition, the detergent-soluble fraction of myelin depends primarily on the combination of Nogo, MAG, and OMgp (30). Spinal cord injury studies with ephrinB3 −/− mice here, in combination with previous studies with Nogo, MAG, OMgp triple knockout mice (30), suggest that all four proteins contribute to in vivo limitation of axonal growth after CNS trauma by myelin. The greatest degree of regeneration and recovery may be achieved through combined interruption of ephrinB3 and NgR1 ligands.…”

Dysfunction of Platelet-derived Growth Factor Receptor α (PDGFRα) Represses the Production of Oligodendrocytes from Arylsulfatase A-deficient Multipotential Neural Precursor Cells

“…Our observations may also be extrapolated to other demyelinating diseases, such as multiple sclerosis, where demyelination could lead to the availability of myelin debris, transforming myelin-derived sulfatides into environmental toxins (31, 89 -91) that may impair remyelination. In this regard, other myelin components, such as myelin-associated glycoprotein, myelin oligodendrocyte glycoprotein, and Nogo A, are known to exert inhibitory functions, decreasing the regenerative capacity of the brain (92)(93)(94).…”