Biological significance of recombination-activating gene 1, RAG1 in optic nerve neuropathy

Although the transcription factor, nuclear factor-kappa-B (NF-B) is known to regulate programed-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-b1p50 spontaneously developed optic neuropathy. We investigated the expression and activation of pro-apoptotic factor(s), which mediate optic nerve neuropathy in Nf-b1p50-deficient mice. Recombination activating gene 1 (RAG1) is known to control the recombination of immunoglobulin V(D)J. Experiments with genetically engineered mice revealed the involvement of RAG1 expression in the programmed-cell death of POU domain protein (POU4f2)/brain-specific homeobox 3A (BRN3a)-positive retinal ganglion cells (RGCs), and also showed the specific effects of a Nf-b1p50-deficient on the activation of Rag1 gene transcription. Furthermore, a genetic analysis of murine neuronal stem-like cells clarified the biological significance of RAG1 in N-methyl-D-aspartate (NMDA)-induced neuronal cell death. The apoptotic inducing factors were detected in human cell line expressing the external molecule of RAG1, and human histopathological examinations with retina tissues revealed the expression of RAG1 in RGCs. Recent studies indicated that RAG1 played a key role in optic nerve neuropathy as a pro-apoptotic candidate in Nf-b1p50deficient mice. These results may lead to new therapeutic targets in optic nerve neuropathy.