Neuronal death signaling pathway: Involvement of Rag1 activation

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 (CNS) remains unknown. We previously reported that mice with a homozygous deficiency for NF-κBp50 spontaneously developed optic neuropathy. We examined the expression and activation of pro-apoptotic factor(s), which mediate optic neuropathy in p50-deficient (p50-/-) mice. Recombination activating gene 1 (Rag1) is known to regulate the recombination of immunoglobulin V(D)J. Experiments with genetically engineered mice revealed the involvement of Rag1 expression in the apoptosis of Brn3a-positive retinal ganglion cells (RGCs), and also showed the specific effects of a p50-deficiency on the activation of Rag1 gene transcription. Furthermore, a genetic analysis of murine neuronal stem-like cells clarified the biological significance of Rag1 in NMDA (N-methyl-D-aspartate)-induced neuronal apoptosis. The apoptotic regulating factors, Bax, and cleaved caspase 3, 8, and 9 were observed in HEK293 cells expressing the external molecule of Rag1, and a human histological examination revealed the expression of Rag1 in RGCs. Recent study indicated that Rag1 played a role in optic neuropathy as a pro-apoptotic candidate in p50-/- mice. This result may lead to new therapeutic targets in optic neuropathy.