title: Physiological significance of recombination-activating gene 1 in neuronal death, especially optic neuropathy.
abstract: Although the transcription factor nuclear factor-κB (NF-κB) is known to regulate cell death and survival, its precise role in cell death within the central nervous system remains unknown. We previously reported that mice with a homozygous deficiency for NF-κBp50 spontaneously develop optic neuropathy. The aim of the present study was to demonstrate the expression and activation of the proapoptotic factor(s) that mediate optic neuropathy in p50-deficient mice. Recombination-activating gene (Rag) 1 is known to activate the recombination of immunoglobulin V(D)J. In this study, experiments with genetically engineered mice revealed the involvement of Rag1 expression in apoptosis of Brn3a-positive retinal ganglion cells, and also demonstrated the specific effect of p50 deficiency on the activation of Rag1 gene transcription. Furthermore, genetic analysis of murine neuronal stem-like cells clarified the biological significance of Rag1 in N-methyl-D-aspartate-induced neuronal apoptosis. We also detected the apoptosis-regulating factors Bax and cleaved caspase 3, 8 and 9 in HEK293 cells transfected-molecule of Rag1, and a human histological examination revealed the expression of Rag1 in retinal ganglion cells. The results of the present study indicate that Rag1 plays a role in optic neuropathy as a proapoptotic candidate in p50-deficient mice. This finding may lead to new therapeutic targets in optic neuropathy.
authors.affiliation: Department of Ophthalmology, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan; Department of Immunology and Infectious Disease, Shinshu University Graduate School of Medicine, Matsumoto, Nagano, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hirano
authors.forename: Toshinori
authors.initials: T
authors.lastname: Murata
authors.forename: Takuma
authors.initials: T
authors.lastname: Hayashi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D055785:Gene Knockdown Techniques; D016654:Genes, RAG-1; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008959:Models, Neurological; D016202:N-Methylaspartate / Q000633:toxicity; D052002:NF-kappa B p50 Subunit / Q000172:deficiency / Q000235:genetics; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009901:Optic Nerve Diseases / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D050819:Transcription Factor Brn-3A / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D052002:NF-kappa B p50 Subunit; C494189:Pou4f1 protein, mouse; D011994:Recombinant Proteins; D050819:Transcription Factor Brn-3A; C064658:RAG-1 protein; D016202:N-Methylaspartate
keywords: NF-κBp50; Rag1; optic neuropathy; programmed cell death; retinal ganglion cell