Development of spontaneous optic neuropathy in NF-kappaBetap50-deficient mice: requirement for NF-kappaBetap50 in ganglion cell survival.
Although the transcription factor NF-kappaBeta is known to regulate cell death and survival, its precise role in cell death within the central nervous system remains unknown. The purpose of this study was to investigate the role of NF-kappaBetap50 in the age-related survival of retinal ganglion cells (RGCs). Eyes of mice with a deleted NF-kappaBetap50 gene and its wild-type mice at each of age were studied by histopathological studies. The number of RGCs was counted using retrograde labelling methods. Mice were subjected to intravitreous injection of N-methyl-D aspartate (NMDA) to induce RGC death. In p50-deficient mice, the number of RGCs significantly decreased with age in total independence of intraocular pressure measurement. Optic nerves of p50-deficient mice showed hypertrophy astrocytes and enlargement of the axons, together with a decreased number of axons. Immunohistochemistry showed a strong expression of glial fibrillary acidic protein. The histological results show obvious excavation of the optic nerve head in p50-deficient mice at 10 months of age. Intravitreal injection of NMDA in young p50-deficient mice damaged RGCs more intensively than in control animals. We further noticed that autoantibodies against RGCs were produced in p50-deficient mice. Our results show that p50 deficiency induced age-related RGC death, indicating a new insight into the role of p50 in the pathophysiology of neuropathy, and further experiments with p50-deficient mice may provide new targets for therapeutic intervention for human glaucoma.
Takahashi
Y
Y
Department of Molecular Oncology and Angiology, Research Center on Ageing and Adaptation, Shinshu University Graduate School of Medicine, Matsumoto-city, Nagano, Japan.
Katai
N
N
Murata
T
T
Taniguchi
S-I
SI
Hayashi
T
T
D000367:Age Factors; D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D015153:Blotting, Western; D002470:Cell Survival; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D015870:Gene Expression; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D007150:Immunohistochemistry; D007429:Intraocular Pressure; D051379:Mice; D008817:Mice, Mutant Strains; D046529:Microscopy, Electron, Transmission; D016202:N-Methylaspartate / Q000633:toxicity; D052002:NF-kappa B p50 Subunit / Q000172:deficiency*; D009900:Optic Nerve / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*; D012165:Retinal Ganglion Cells / Q000276:immunology / Q000378:metabolism* / Q000473:pathology*
D001323:Autoantibodies; D001324:Autoantigens; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D052002:NF-kappa B p50 Subunit; D016202:N-Methylaspartate