Mechanisms of myelin regeneration inhibition

Injury to the vertebrate central nervous system (CNS) causes permanent deficits due to the inability of neurons to regenerate lost connections. Many studies have implicated the CNS environment as a source of molecules that block neuronal outgrowth, and thus regeneration. This dissertation initially deals with the identification of a novel inhibitory component of CNS myelin through the use of a proteomic approach. Using a novel glycosylphosphatidylinositol (GPI) proteomic-based strategy we identified oligodendrocyte-myelin glycoprotein (OMgp) as myelin inhibitor that is a physiological ligand to the Nogo-receptor (NgR). In the next phase of my thesis work, we decided to take an unbiased approach to studying the signaling mechanisms that underlie myelin inhibition. Using a known-target drug screen I was able to identify the epidermal growth factor receptor (EGFR) as a major signaling component of myelin inhibition. EGFR signaling was NgR and calcium-dependent. Furthermore, application of EGFR inhibitors to crushed optic nerves in vivo promoted significant outgrowth of retinal ganglion fibers. Taken together, my dissertation research has provided insights into the mechanism of myelin regeneration inhibition as well as provided a rational basis for potential therapy of CNS injury.