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Optic Nerve Transection: A Model of Adult Neuron Apoptosis in the Central Nervous System
Published on: May 12, 2011
Physiological significance of recombination-activating gene 1 in neuronal death, especially optic neuropathy
Takao Hirano1, Toshinori Murata, Takuma Hayashi
1Department 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.
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.
Insights
Recombination-activating gene (Rag) 1 mediates optic neuropathy in mice lacking NF-κBp50. This study identifies Rag1 as a proapoptotic factor, potentially offering new therapeutic targets for optic neuropathy.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Nuclear factor-κB (NF-κB) regulates cell death and survival, but its role in central nervous system cell death is unclear.
- Mice deficient in NF-κBp50 develop spontaneous optic neuropathy, suggesting a role for this pathway in retinal ganglion cell survival.
Purpose of the Study:
- To investigate the proapoptotic factors mediating optic neuropathy in NF-κBp50-deficient mice.
- To elucidate the role of Recombination-activating gene (Rag) 1 in NF-κB-dependent optic nerve cell death.
Main Methods:
- Utilized genetically engineered mice lacking NF-κBp50.
- Conducted genetic analysis of murine neuronal stem-like cells.
- Performed HEK293 cell transfections and human histological examinations.
Main Results:
- Rag1 expression was involved in the apoptosis of Brn3a-positive retinal ganglion cells in p50-deficient mice.
- p50 deficiency specifically affected Rag1 gene transcription activation.
- Rag1 demonstrated a role in N-methyl-D-aspartate-induced neuronal apoptosis.
- Apoptosis-regulating factors Bax and cleaved caspases were detected in Rag1-transfected cells.
Conclusions:
- Rag1 acts as a proapoptotic factor in NF-κBp50-deficient mice, contributing to optic neuropathy.
- These findings suggest Rag1 as a potential therapeutic target for optic neuropathy.
