Stimulating Axon Regeneration by Blocking EGF Receptor Activity

Children's Hospital Boston
posted on 10/02/2011

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Inhibitory molecules associated with myelin and the glial scar limit axon regeneration in the adult central nervous system (CNS), but the underlying signaling mechanisms of regeneration inhibition are not fully understood. Dr. He has shown that suppressing the kinase function of the epidermal growth factor receptor (EGFR) blocks the activities of both myelin inhibitors and chondroitin sulfate proteoglycans in inhibiting neurite outgrowth. In addition, regeneration inhibitors trigger the phosphorylation of EGFR in a calcium-dependent manner. Local administration of EGFR inhibitors promotes significant regeneration of injured optic nerve fibers, pointing to a promising therapeutic avenue for enhancing axon regeneration after CNS injury. || To confirm our observations, Dr. He's lab tested two well-characterized EGFR inhibitors, a competitive inhibitor AG1478, and an irreversible inhibitor PD168393 (18) in neurite outgrowth assays. Both inhibitors effectively promoted neurite outgrowth from both CGNs and dorsal root ganglion (DRG) neurons when grown on an immobilized substrate of either whole myelin or individual myelin inhibitors. In contrast, none of the treatments affected neurite outgrowth on a control poly- D-lysine (PDL) substrate. Similarly, EGFR kinase inhibitors were able to block neurite outgrowth inhibition by myelin in retinal explant cultures grown in a collagen matrix laden with myelin. Although retinal explants are mixtures of retinal ganglion cells (RGCs) and other cells, dissociated cultures contained primarily CGNs and DRG neurons. Thus, it is likely that EGFR inhibitors act directly on neurons to block their inhibitory responses to myelin inhibitors.