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

被引:82
作者
Jorgensen, Jesper Roland [1 ]
Fransson, Anette [2 ]
Fjord-Larsen, Lone [1 ]
Thompson, Lachlan H. [3 ]
Houchins, Jeffrey P. [4 ]
Andrade, Nuno [5 ]
Torp, Malene [1 ]
Kalkkinen, Nisse [6 ]
Andersson, Elisabet [7 ]
Lindvall, Olle [5 ]
Ulfendahl, Mats [2 ]
Brunak, Soren [8 ,9 ]
Johansen, Teit E. [1 ]
Wahlberg, Lars U. [1 ]
机构
[1] NsGene AS, DK-2750 Ballerup, Denmark
[2] Karolinska Inst, Ctr Hearing & Commun Res, Dept Clin Sci Invent & Technol, S-17176 Stockholm, Sweden
[3] Univ Melbourne, Florey Neurosci Inst, Parkville, Vic 3010, Australia
[4] R&D Syst Inc, Minneapolis, MN 55413 USA
[5] Univ Lund Hosp, Lab Neurogenesis & Cell Therapy, S-22184 Lund, Sweden
[6] Univ Helsinki, Inst Biotechnol, Prot Chem Res Grp, FIN-00014 Helsinki, Finland
[7] Karolinska Inst, S-17177 Stockholm, Sweden
[8] Tech Univ Denmark, Ctr Biol Sequence Anal, DK-2800 Lyngby, Denmark
[9] Univ Copenhagen, Fac Hlth Sci, NFF Ctr Prot Res, DK-2200 Copenhagen, Denmark
基金
瑞典研究理事会;
关键词
Floor plate; Meteorin; Migration; Neurotrophic; Trophic factor; Spiral ganglion; Novel protein; GENE-EXPRESSION; STEM-CELLS; METEORIN; MOUSE; PROTEIN; IDENTIFICATION; EVOLUTION; MEMBER; TRK;
D O I
10.1016/j.expneurol.2011.09.027
中图分类号
Q189 [神经科学];
学科分类号
071006 ;
摘要
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 la. 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. (C) 2011 Elsevier Inc. All rights reserved.
引用
收藏
页码:172 / 181
页数:10
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