title: Modifying lipid rafts promotes regeneration and functional recovery.
abstract: 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.
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Nardos G
authors.initials: NG
authors.lastname: Tassew
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Mothe
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Anatomy, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada.
authors.forename: Alireza P
authors.initials: AP
authors.lastname: Shabanzadeh
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Paromita
authors.initials: P
authors.lastname: Banerjee
authors.affiliation: Department of Anatomy, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Ophthalmology, Faculty of Medicine, 340 College Street, University of Toronto, Toronto, ON M5T 3A9, Canada.
authors.forename: Paulo D
authors.initials: PD
authors.lastname: Koeberle
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Ophthalmology, Faculty of Medicine, 340 College Street, University of Toronto, Toronto, ON M5T 3A9, Canada; Samuel Lunenfeld Research Institute, Mount Sinai Hospital, 982 University Avenue, Toronto, ON M5G 1X5, Canada.
authors.forename: Rod
authors.initials: R
authors.lastname: Bremner
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada.
authors.forename: Charles H
authors.initials: CH
authors.lastname: Tator
authors.affiliation: Toronto Western Research Institute, Genetics and Development Division, Krembil Discovery Tower, KDT-8-418, 60 Leonard Street, Toronto, ON M5T 2S8, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Toronto, ON M5S 1A8, Canada; Department of Ophthalmology, Faculty of Medicine, 340 College Street, University of Toronto, Toronto, ON M5T 3A9, Canada. Electronic address: pmonnier@uhnres.utoronto.ca.
authors.forename: Philippe P
authors.initials: PP
authors.lastname: Monnier
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology; D002645:Chickens; D005260:Female; D020439:Growth Cones / Q000502:physiology; D018942:Macrolides; D021962:Membrane Microdomains / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism; D009046:Motor Neurons / Q000502:physiology; D009416:Nerve Regeneration; D009419:Nerve Tissue Proteins / Q000502:physiology; D009900:Optic Nerve / Q000473:pathology / Q000503:physiopathology; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000502:physiology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000503:physiopathology
chemical_list: D018942:Macrolides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C091279:neogenin; C114125:apoptolidin