UC San Diego

Functional recovery following central nervous system (CNS) trauma is often restricted by stagnant growth of severed axons. A number of studies indicate that the presence of endogenous inhibitory molecules from astroglial scarring and myelin debris contribute to the diminished regenerative capacity of CNS axons. To assess the roles of two specific myelin-derived inhibitors - Nogo and myelin- associated glycoprotein (MAG) - and their common receptor, NgR, in the regrowth of mature axons, we evaluated complete spinal transection models of single NgR and triple NgR/Nogo/MAG knockout (KO) mice. Previous studies of single NgR mutants using a dorsal hemisection model have shown that despite possible displays of improved behavioral recovery, there is no detectable regeneration of the corticospinal tract (CST). We focused our analysis on serotonergic (5-HT) fibers because previous studies suggest that these axons have a high intrinsic regenerative capability. Our results indicate that though there is an increase in 5-HT fiber sprouting within the injury site of single NgR KO mice, there is no significant enhancement in 5-HT fiber regeneration beyond the injury site in either NgR single mutants or NgR/Nogo/MAG triple mutant mice. These data suggest that disrupting two major myelin-derived axon growth inhibitors together with their common receptor NgR remains insufficient to elicit enhanced axon regeneration in the adult mammalian CNS. This calls for a re-examination of this molecular pathway for therapeutic development to treat spinal cord injury