TY - JOUR

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

A1 - Jørgensen,Jesper Roland

A1 - Fransson,Anette

A1 - Fjord-Larsen,Lone

A1 - Thompson,Lachlan H.

A1 - Houchins,Jeffrey P.

A1 - Andrade,Nuno

A1 - Torp,Malene

A1 - Kalkkinen,Nisse

A1 - Andersson,Elisabet

A1 - Lindvall,Olle

A1 - Ulfendahl,Mats

A1 - Brunak,Søren

A1 - Johansen,Teit E.

A1 - Wahlberg,Lars U.

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.

PB - Academic Press

PY - 2012

Y1 - 2012

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.

KW - Floor plate

KW - Meteorin

KW - Novel protein

KW - Trophic factor

KW - Neurotrophic

KW - Spiral ganglion

KW - Migration

U2 - 10.1016/j.expneurol.2011.09.027

DO - 10.1016/j.expneurol.2011.09.027

JO - Experimental Neurology

JF - Experimental Neurology

SN - 0014-4886

IS - 1

VL - 233

SP - 172

EP - 181

ER -