Physiological significance of recombination-activating gene 1 in neuronal death, especially optic neuropathy

FEBS J. 2015 Jan;282(1):129-41. doi: 10.1111/febs.13109. Epub 2014 Nov 13.


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.

Keywords: NF-κBp50; Rag1; optic neuropathy; programmed cell death; retinal ganglion cell.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Apoptosis / physiology
  • Gene Knockdown Techniques
  • Genes, RAG-1
  • HEK293 Cells
  • Homeodomain Proteins / antagonists & inhibitors
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Models, Neurological
  • N-Methylaspartate / toxicity
  • NF-kappa B p50 Subunit / deficiency
  • NF-kappa B p50 Subunit / genetics
  • Nerve Degeneration / genetics
  • Nerve Degeneration / metabolism
  • Nerve Degeneration / pathology
  • Optic Nerve Diseases / etiology
  • Optic Nerve Diseases / pathology*
  • Optic Nerve Diseases / physiopathology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • Retinal Ganglion Cells / drug effects
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology
  • Signal Transduction
  • Transcription Factor Brn-3A / metabolism


  • Homeodomain Proteins
  • NF-kappa B p50 Subunit
  • Pou4f1 protein, mouse
  • Recombinant Proteins
  • Transcription Factor Brn-3A
  • RAG-1 protein
  • N-Methylaspartate