Modifying Lipid Rafts Promotes Regeneration and Functional Recovery

Ideal strategies to ameliorate CNS damage should promote both neuronal survival and axon regeneration. The receptor Neogenin promotes neuronal apoptosis. Its ligand prevents death, but the resulting repulsive guidance molecule a (RGMa)-Neogenin interaction also inhibits axonal growth, countering any prosurvival benefits. Here, we explore strategies to inhibit Neogenin, thus simultaneously enhancing survival and regeneration. We show that bone morphogenetic protein (BMP) and RGMa-dependent recruitment of Neogenin into lipid rafts requires an interaction between RGMa and Neogenin subdomains. RGMa or Neogenin peptides that prevent this interaction, BMP inhibition by Noggin, or reduction of membrane cholesterol all block Neogenin raft localization, promote axon outgrowth, and prevent neuronal apoptosis. Blocking Neogenin raft association influences axonal pathfinding, enhances survival in the developing CNS, and promotes survival and regeneration in the injured adult optic nerve and spinal cord. Moreover, lowering cholesterol disrupts rafts and restores locomotor function after spinal cord injury. These data reveal a unified strategy to promote both survival and regeneration in the CNS. [Display omitted] •A cis interaction between RGMa and Neogenin associates Neogenin with lipid rafts•Altering Neogenin presence in lipid rafts promotes survival and axonal growth•Cholesterol depletion promotes regeneration after CNS injuries Neuronal regeneration is very poor following CNS injuries. This is mostly due to the presence of extracellular proteins, such as RGMa, that hamper regeneration. In this study, Tassew et al. show that Neogenin, a receptor for RGMa, requires association with cholesterol-rich cell membrane domains to induce neuronal death and block axonal regeneration. They show that blocking Neogenin association with these membrane compartments allows for functional recovery following CNS injuries.