title: Inhibition of repulsive guidance molecule, RGMa, increases afferent synapse formation with auditory hair cells.
abstract: The peripheral fibers that extend from auditory neurons to hair cells are sensitive to damage, and replacement of the fibers and their afferent synapse with hair cells would be of therapeutic interest. Here, we show that RGMa, a repulsive guidance molecule previously shown to play a role in the development of the chick visual system, is expressed in the developing, newborn, and mature mouse inner ear. The effect of RGMa on synaptogenesis between afferent neurons and hair cells, from which afferent connections had been removed, was assessed. Contact of neural processes with hair cells and elaboration of postsynaptic densities at sites of the ribbon synapse were increased by treatment with a blocking antibody to RGMa, and pruning of auditory fibers to achieve the mature branching pattern of afferent neurons was accelerated. Inhibition by RGMa could thus explain why auditory neurons have a low capacity to regenerate peripheral processes: postnatal spiral ganglion neurons retain the capacity to send out processes that respond to signals for synapse formation, but expression of RGMa postnatally appears to be detrimental to regeneration of afferent hair cell innervation and antagonizes synaptogenesis. Increased synaptogenesis after inhibition of RGMa suggests that manipulation of guidance or inhibitory factors may provide a route to increase formation of new synapses at deafferented hair cells.
authors.affiliation: Department of Otology and Laryngology, Harvard Medical School, Boston, Massachusetts, 02115; Eaton-Peabody Laboratory, Massachusetts Eye and Ear Infirmary, Boston, Massachusetts, 02114.
authors.forename: Aurore
authors.initials: A
authors.lastname: Brugeaud
authors.forename: Mingjie
authors.initials: M
authors.lastname: Tong
authors.forename: Li
authors.initials: L
authors.lastname: Luo
authors.forename: Albert S B
authors.initials: AS
authors.lastname: Edge
mesh_terms: D000429:Alcohol Oxidoreductases; D000818:Animals; D001306:Auditory Pathways / Q000166:cytology / Q000254:growth & development* / Q000502:physiology*; D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D005455:Fluorescent Antibody Technique; D058851:GPI-Linked Proteins / Q000378:metabolism; D051528:Guanylate Kinases / Q000378:metabolism; D006198:Hair Cells, Auditory / Q000166:cytology / Q000502:physiology*; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D000081412:Myosin VIIa; D009218:Myosins / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D009475:Neurons, Afferent / Q000166:cytology / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013136:Spiral Ganglion / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D013569:Synapses / Q000502:physiology*
chemical_list: D056970:Co-Repressor Proteins; D004268:DNA-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; C000631456:Myo7a protein, mouse; D000081412:Myosin VIIa; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D010750:Phosphoproteins; C483496:Rgma protein, mouse; C091279:neogenin; D000429:Alcohol Oxidoreductases; C111341:Ctbp2 protein, mouse; D051528:Guanylate Kinases; D009218:Myosins
keywords: RGMa; cochlear regeneration; cochlear synaptogenesis; spiral ganglion neuron