title: RA-RAR-β counteracts myelin-dependent inhibition of neurite outgrowth via Lingo-1 repression.
abstract: After an acute central nervous system injury, axonal regeneration is limited as the result of a lack of neuronal intrinsic competence and the presence of extrinsic inhibitory signals. The injury fragments the myelin neuronal insulating layer, releasing extrinsic inhibitory molecules to signal through the neuronal membrane-bound Nogo receptor (NgR) complex. In this paper, we show that a neuronal transcriptional pathway can interfere with extrinsic inhibitory myelin-dependent signaling, thereby promoting neurite outgrowth. Specifically, retinoic acid (RA), acting through the RA receptor β (RAR-β), inhibited myelin-activated NgR signaling through the transcriptional repression of the NgR complex member Lingo-1. We show that suppression of Lingo-1 was required for RA-RAR-β to counteract extrinsic inhibition of neurite outgrowth. Furthermore, we confirm in vivo that RA treatment after a dorsal column overhemisection injury inhibited Lingo-1 expression, specifically through RAR-β. Our findings identify a novel link between RA-RAR-β-dependent proaxonal outgrowth and inhibitory NgR complex-dependent signaling, potentially allowing for the development of molecular strategies to enhance axonal regeneration after a central nervous system injury.
authors.affiliation: Laboratory for NeuroRegeneration and Repair, Center for Neurology, Hertie Institute for Clinical Brain Research and 2 Graduate School for Cellular and Molecular Neuroscience, University of Tuebingen, 72074 Tuebingen, Germany.
authors.forename: Radhika
authors.initials: R
authors.lastname: Puttagunta
authors.forename: André
authors.initials: A
authors.lastname: Schmandke
authors.forename: Elisa
authors.initials: E
authors.lastname: Floriddia
authors.forename: Perrine
authors.initials: P
authors.lastname: Gaub
authors.forename: Natalie
authors.initials: N
authors.lastname: Fomin
authors.forename: Norbert B
authors.initials: NB
authors.lastname: Ghyselinck
authors.forename: Simone
authors.initials: S
authors.lastname: Di Giovanni
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D009186:Myelin Sheath / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D016501:Neurites / Q000378:metabolism* / Q000648:ultrastructure; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014212:Tretinoin / Q000378:metabolism / Q000502:physiology*
chemical_list: C523678:LINGO1 protein, mouse; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D018168:Receptors, Retinoic Acid; C082925:retinoic acid receptor beta; D014212:Tretinoin