Abstract
Axon regeneration in the injured adult CNS is reportedly inhibited by myelin-derived inhibitory molecules, after binding to a receptor complex comprised of the Nogo-66 receptor (NgR1) and two transmembrane co-receptors p75/TROY and LINGO-1. However, the post-injury expression pattern for LINGO-1 is inconsistent with its proposed function. We demonstrated that AMIGO3 levels were significantly higher acutely than those of LINGO-1 in dorsal column lesions and reduced in models of dorsal root ganglion neuron (DRGN) axon regeneration. Similarly, AMIGO3 levels were raised in the retina immediately after optic nerve crush, whilst levels were suppressed in regenerating optic nerves, induced by intravitreal peripheral nerve implantation. AMIGO3 interacted functionally with NgR1-p75/TROY in non-neuronal cells and in brain lysates, mediating RhoA activation in response to CNS myelin. Knockdown of AMIGO3 in myelin-inhibited adult primary DRG and retinal cultures promoted disinhibited neurite growth when cells were stimulated with appropriate neurotrophic factors. These findings demonstrate that AMIGO3 substitutes for LINGO-1 in the NgR1-p75/TROY inhibitory signalling complex and suggests that the NgR1-p75/TROY-AMIGO3 receptor complex mediates myelin-induced inhibition of axon growth acutely in the CNS. Thus, antagonizing AMIGO3 rather than LINGO-1 immediately after CNS injury is likely to be a more effective therapeutic strategy for promoting CNS axon regeneration when combined with neurotrophic factor administration.
Highlights
CNS axon regeneration is limited by a low intrinsic growth capacity of mature neurons and the presence of a non-permissive environment in the injured adult CNS that inhibits axon growth [1,2,3,4]
Immunohistochemistry for AMIGO (Figure 1E), AMIGO2 (Fig. 1F), AMIGO3 (Fig. 1G) and LINGO-1 (Fig. 1H) in sections of DRG taken at 1 day after dorsal column (DC) crush, mirrored changes observed for mRNA levels and demonstrated that AMIGO3, but not AMIGO proteins were elevated in dorsal root ganglion neuron (DRGN)
We demonstrate a novel role for AMIGO3 as a molecule that participates in the NgR1-p75/TROY receptor complex that signals axon growth inhibition and show that its expression levels are consistent with a physiological function in this complex in the injured CNS
Summary
CNS axon regeneration is limited by a low intrinsic growth capacity of mature neurons and the presence of a non-permissive environment in the injured adult CNS that inhibits axon growth [1,2,3,4]. All three myelin inhibitors bind to a common receptor, Nogo-66 receptor (NgR1) that can signal inhibition and growth cone collapse through the RhoGTPase pathway by associating with two signal transducing binding partners, p75 (the low affinity neurotrophin receptor) and LINGO-1 (leucine rich-repeat and immunoglobulin domain-containing, Nogo receptor interacting protein) [1,3,7,8,9,10]. Expression of AMIGO correlates with the onset of CNS myelination during postnatal development and localises to axonal fibre tracts, while a substrate bound AMIGO-immunoglobulin fusion protein which antagonizes AMIGO, promotes neurite outgrowth of hippocampal neurons [14], but little is known about the axogenic properties of AMIGO2 and AMIGO3
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