title: Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo.
abstract: Neurotrophic factors are secreted proteins responsible for migration, growth and survival of neurons during development, and for maintenance and plasticity of adult neurons. Here we present a novel secreted protein named Cometin which together with Meteorin defines a new evolutionary conserved protein family. During early mouse development, Cometin is found exclusively in the floor plate and from E13.5 also in dorsal root ganglions and inner ear but apparently not in the adult nervous system. In vitro, Cometin promotes neurite outgrowth from dorsal root ganglion cells which can be blocked by inhibition of the Janus or MEK kinases. In this assay, additive effects of Cometin and Meteorin are observed indicating separate receptors. Furthermore, Cometin supports migration of neuroblasts from subventricular zone explants to the same extend as stromal cell derived factor 1a. Given the neurotrophic properties in vitro, combined with the restricted inner ear expression during development, we further investigated Cometin in relation to deafness. In neomycin deafened guinea pigs, two weeks intracochlear infusion of recombinant Cometin supports spiral ganglion neuron survival and function. In contrast to the control group receiving artificial perilymph, Cometin treated animals retain normal electrically-evoked brainstem response which is maintained several weeks after treatment cessation. Neuroprotection is also evident from stereological analysis of the spiral ganglion. Altogether, these studies show that Cometin is a potent new neurotrophic factor with therapeutic potential.
authors: NsGene A/S, 2750 Ballerup, Denmark. JRJ@NSGENE.DK
authors: Jesper Roland
authors: JR
authors: Jørgensen
authors: Anette
authors: A
authors: Fransson
authors: Lone
authors: L
authors: Fjord-Larsen
authors: Lachlan H
authors: LH
authors: Thompson
authors: Jeffrey P
authors: JP
authors: Houchins
authors: Nuno
authors: N
authors: Andrade
authors: Malene
authors: M
authors: Torp
authors: Nisse
authors: N
authors: Kalkkinen
authors: Elisabet
authors: E
authors: Andersson
authors: Olle
authors: O
authors: Lindvall
authors: Mats
authors: M
authors: Ulfendahl
authors: Søren
authors: S
authors: Brunak
authors: Teit E
authors: TE
authors: Johansen
authors: Lars U
authors: LU
authors: Wahlberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000831:Animals, Newborn; D002465:Cell Movement / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002490:Central Nervous System / Q000196:embryology / Q000378:metabolism; D002552:Cerebral Ventricles / Q000166:cytology; D002851:Chromatography, High Pressure Liquid; D003001:Cloning, Molecular; D017077:Culture Media, Conditioned / Q000737:chemistry; D003638:Deafness / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D000089622:Doublecortin Domain Proteins; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008855:Microscopy, Electron, Scanning / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009355:Neomycin / Q000633:toxicity; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000494:pharmacology; D058953:Neural Stem Cells / Q000187:drug effects* / Q000648:ultrastructure; D016501:Neurites / Q000187:drug effects* / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000648:ultrastructure; D009479:Neuropeptides / Q000378:metabolism; D051381:Rats; D013136:Spiral Ganglion / Q000166:cytology*; D053719:Tandem Mass Spectrometry; D014162:Transfection / Q000379:methods
chemical_list: D017077:Culture Media, Conditioned; D000089622:Doublecortin Domain Proteins; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; C570859:cometin protein, mouse; C502098:meteorin protein, mouse; D009355:Neomycin