The inhibitory activities associated with myelin have been demonstrated to be a major obstacle to successful axon regeneration. Recent studies from our laboratory have identified Nogo, myelin associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) as specific components of myelin that collectively account for the majority of this inhibitory activity. Strikingly, all three molecules bind to a common GPI-linked Nogo-66 receptor (NgR) with high affinity, with signal transduction across the axonal membrane mediated by two transmembrane co-receptors, including a TNF receptor family member p75 and a newly-identified protein Lingo-1. However, it remains unclear how these two co-receptors relay inhibitory signals across the axonal membrane. Interestingly, p75 expression is limited to certain subpopulations of mature neurons in the adult nervous system, suggesting the existence of other functional equivalent(s) of p75 that might mediate the inhibitory activity of myelin on mature neurons. Our preliminary results suggest that TROY, a newly-identified member of the TNF receptor family that is selectively expressed in the adult nervous system, can form a physical and functional receptor complex with NgR and Lingo-1 to mediate cellular responses to myelin inhibitors in non-neuronal cells. In addition, a truncated TROY lacking the intracellular domain of TROY can efficiently block neuronal responses to myelin inhibitors. Thus, we hypothesize that TROY might be a p75 homologue that functions as a NgR co-receptor. Although Lingo-1, TROY, and NgR have been shown to function together to mediate myelin inhibition, the precise mechanism by which Lingo-1 and TROY transmit an inhibitory signal remains largely unknown. The objective of this study is to investigate how two of the receptor components (p75/TROY and Lingo-1) transmit inhibitory signals across the cell membrane to regulate the process of axon regeneration. The specific aims of this study include: 1. To determine whether TROY is a p75-equivalent NgR co-receptor. 2. To examine the contribution of Lingo-1 in the signaling pathway for myelin inhibition. 3. To examine the involvement of TRAF/JNK, two signaling molecules that act downstream of TROY and Lingo-1, in mediating myelin signaling.
