Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo

Jesper Roland Jørgensen; Anette Fransson; Lone Fjord-Larsen; Lachlan H Thompson; Jeffrey P Houchins; Nuno Andrade; Malene Torp; Nisse Kalkkinen; Elisabet Andersson; Olle Lindvall; Mats Ulfendahl; Søren Brunak; Teit E Johansen; Lars U Wahlberg

doi:10.1016/j.expneurol.2011.09.027

Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo

Jesper Roland Jørgensen, Anette Fransson, Lone Fjord-Larsen, Lachlan H Thompson, Jeffrey P Houchins, Nuno Andrade, Malene Torp, Nisse Kalkkinen, Elisabet Andersson, Olle Lindvall, Mats Ulfendahl, Søren Brunak, Teit E Johansen, Lars U Wahlberg

30 Citations (Scopus)

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.

Original language	English
Journal	Experimental Neurology
Volume	233
Issue number	1
Pages (from-to)	172-81
Number of pages	10
ISSN	0014-4886
DOIs	https://doi.org/10.1016/j.expneurol.2011.09.027
Publication status	Published - Jan 2012

Keywords

Amino Acid Sequence
Animals
Animals, Newborn
Cell Movement
Cell Survival
Cells, Cultured
Central Nervous System
Cerebral Ventricles
Chromatography, High Pressure Liquid
Cloning, Molecular
Culture Media, Conditioned
Deafness
Disease Models, Animal
Dose-Response Relationship, Drug
Embryo, Mammalian
Enzyme Inhibitors
Female
Gene Expression Regulation, Developmental
Guinea Pigs
Humans
Male
Mice
Microscopy, Electron, Scanning
Microtubule-Associated Proteins
Neomycin
Nerve Growth Factors
Nerve Tissue Proteins
Neural Stem Cells
Neurites
Neurons
Neuropeptides
Rats
Spiral Ganglion
Tandem Mass Spectrometry
Transfection

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10.1016/j.expneurol.2011.09.027

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Jørgensen, J. R., Fransson, A., Fjord-Larsen, L., Thompson, L. H., Houchins, J. P., Andrade, N., Torp, M., Kalkkinen, N., Andersson, E., Lindvall, O., Ulfendahl, M., Brunak, S., Johansen, T. E., & Wahlberg, L. U. (2012). Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. Experimental Neurology, 233(1), 172-81. https://doi.org/10.1016/j.expneurol.2011.09.027

Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo. / Jørgensen, Jesper Roland; Fransson, Anette; Fjord-Larsen, Lone et al.

In: Experimental Neurology, Vol. 233, No. 1, 01.2012, p. 172-81.

Research output: Contribution to journal › Journal article › Research › peer-review

Jørgensen, JR, Fransson, A, Fjord-Larsen, L, Thompson, LH, Houchins, JP, Andrade, N, Torp, M, Kalkkinen, N, Andersson, E, Lindvall, O, Ulfendahl, M, Brunak, S, Johansen, TE & Wahlberg, LU 2012, 'Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo', Experimental Neurology, vol. 233, no. 1, pp. 172-81. https://doi.org/10.1016/j.expneurol.2011.09.027

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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.",

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T1 - Cometin is a novel neurotrophic factor that promotes neurite outgrowth and neuroblast migration in vitro and supports survival of spiral ganglion neurons in vivo

AU - Jørgensen, Jesper Roland

AU - Fransson, Anette

AU - Fjord-Larsen, Lone

AU - Thompson, Lachlan H

AU - Houchins, Jeffrey P

AU - Andrade, Nuno

AU - Torp, Malene

AU - Kalkkinen, Nisse

AU - Andersson, Elisabet

AU - Lindvall, Olle

AU - Ulfendahl, Mats

AU - Brunak, Søren

AU - Johansen, Teit E

AU - Wahlberg, Lars U

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N2 - 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.

AB - 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.

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KW - Chromatography, High Pressure Liquid

KW - Cloning, Molecular

KW - Culture Media, Conditioned

KW - Deafness

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Embryo, Mammalian

KW - Enzyme Inhibitors

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Guinea Pigs

KW - Humans

KW - Male

KW - Mice

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KW - Neomycin

KW - Nerve Growth Factors

KW - Nerve Tissue Proteins

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KW - Neuropeptides

KW - Rats

KW - Spiral Ganglion

KW - Tandem Mass Spectrometry

KW - Transfection

U2 - 10.1016/j.expneurol.2011.09.027

DO - 10.1016/j.expneurol.2011.09.027

M3 - Journal article

C2 - 21985865

SN - 0014-4886

VL - 233

SP - 172

EP - 181

JO - Experimental Neurology

JF - Experimental Neurology

IS - 1

ER -

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

Keywords

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