UC San Diego

Adult central nervous system (CNS) axons fail to regenerate after injury, and one of the hurdles limiting CNS regeneration is the presence of potent inhibitory molecules in adult white matter. However, multipotent neural progenitor cells exhibit remarkably extensive axonal elongation through adult white matter when grafted in vivo (Lu et al., 2012), suggesting either that early stage neurons are not inhibited by, or are actually stimulated by, white matter. To address these possibilities, we used multipotent neural progenitor cells (NPCs) isolated from E12 mouse spinal cords for cell culture on adult CNS myelin in vitro and compared findings to cells cultured on non-myelin substrates. Compared to cells cultured in the absence of myelin, adult DRG neurons exhibited a reduction in neurite outgrowth on myelin, whereas NPC cultures exhibited a significant increase in neurite length. While adult neurite growth inhibition is mediated in part by interactions with Nogo receptors and their ligands, Nogo, MAG, and OMgp, we found no change in neurite outgrowth when neural progenitor cells were plated on Nogo, MAG, or OMgp-deficient myelin compared to wild- type myelin. This suggests that classic adult myelin- related inhibitory mechanisms are not involved in facilitation of developing neuronal process outgrowth, and that other mechanisms are likely to be involved. Overall, these findings indicate that one of the mechanisms underlying the remarkable growth ability of early stage neurons in the injured adult CNS is a stimulatory influence of adult myelin