Failure of axonal regeneration in the adult mammalian CNS is partly due to the inhibitory effect of molecules associated with CNS myelin and the glial scar, but the underlying intracellular signalling mechanisms are not clear. Writing in Science, Koprivica and colleagues show that inhibition of regeneration is mediated by activation of the epidermal growth factor receptor (EGFR), and that EGFR inhibitors promote significant repair of injured optic nerve fibres.
The potent inhibitory effect of myelin and the glial scar on axonal growth can be easily studied in culture. When neurons are grown in the presence of either myelin or the active component of the glia scar, chondroitin sulphate proteoglycans (CSPGs), they will have little neurite arborization compared with their couterparts grown in control conditions. This easy assay has allowed Koprivica et al. to screen ∼400 well characterized small molecules for their ability to reverse the inhibitory activity of myelin and CSPGs.
Surprisingly, several EGFR kinase inhibitors, including AG1478, PD168393 and Tarceva, enhanced neurite extension from dissociated rat cerebellar granule and dorsal root ganglion (DRG) neurons grown in the presence of either myelin or CSPGs. Moreoever, axonal growth of DRG neurons expressing a dominant-negative mutant form of EGFR was no longer blocked by myelin or CSPGs, indicating that EGFR kinase activity might be involved in the inhibition of regeneration.
This prompted the researchers to test the effect of myelin on EGFR phosphorylation in serum-starved cerebellar granule neurons. Both Nogo66 and oligodendrocyte myelin glycoprotein — myelin-associated inhibitory proteins — triggered rapid EGFR phosphorylation. This effect was not seen in neurons overexpressing a dominant-negative mutant form of NgR, the common ligand-binding component of the receptor complexes, which indicates that NgR or its functional homologues might be necessary for EGFR activation.
Do EGFR inhibitors have an effect on nerve repair in vivo? To test this, Koprivica et al. crushed the optic nerve in adult mice and applied gelform containing PD168393 at the lesion site immediately after injury. Two weeks later, there was substantial axonal growth in animals treated with the EGFR inhibitor, resulting in a ninefold increase in the number of regenerating fibres 0.25 μm beyond the injury site compared with the control.
This surprising finding has important therapeutic implications for patients with spinal or other CNS injuries. As one of the EGFR inhibitors, Tarceva, has been approved by the US Federal Drug Administration for the treatment of lung cancer, its efficacy in nerve repair may soon be tested in clinical trials.
ORIGINAL RESEARCH PAPER
Koprivica, V. et al. EGFR activation mediates inhibition of axon regeneration by myelin and chondroitin sulfate proteoglycans. Science 310, 106–110 (2005)
Filbin, M. T. Myelin-associated inhibitors of axonal regeneration in the adult mammalian CNS. Nature Rev. Neurosci. 4, 703–713 (2003)
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Qiu, J. A new stop signal. Nat Rev Neurosci 6, 913 (2005). https://doi.org/10.1038/nrn1811