The repulsive guidance molecule, RGMa, promotes retinal ganglion cell survival in vitro and in vivo

Neuroscience. 2010 Aug 11;169(1):495-504. doi: 10.1016/j.neuroscience.2010.04.079. Epub 2010 May 8.

Abstract

The repulsive guidance molecule, RGMa, and its receptor Neogenin, regulate neuronal cell death during development, but little is known about their expression and roles in the adult CNS. Here, we show that Neogenin is expressed in the adult rodent retina, particularly on retinal ganglion cells. To determine whether the Neogenin/RGMa pathway is important in the fully developed retina, we examined its contribution to damage-induced neurodegeneration. The effects of RGMa on survival of retinal ganglion cells (RGCs) were examined in vitro and in vivo. Using cultured whole-mount retinal explants, we showed that the addition of RGMa increased RGC survival and that this effect was mediated by the Neogenin receptor. Immunohistochemical analysis indicated that the inhibition of cell death by RGMa resulted from reduced caspase-3 activation. Then, using an in vivo model of RGC apoptosis after optic nerve transection, we demonstrated that intraocular injection of RGMa at 3 and 7 days after axotomy greatly reduced RGC death 14 days postaxotomy. This study provides the first evidence that RGMa is a molecular target for neuroprotection in retinal pathologies, and suggests that targeting "dependence receptors" such as Neogenin has therapeutic potential for the treatment of neuropathologies in the adult CNS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Axotomy
  • Caspase 3 / physiology
  • Cell Survival / drug effects
  • Cells, Cultured / cytology
  • Cells, Cultured / drug effects
  • Cloning, Molecular
  • Female
  • GPI-Linked Proteins / physiology
  • Membrane Proteins / drug effects
  • Membrane Proteins / immunology
  • Membrane Proteins / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Nerve Degeneration / genetics
  • Nerve Degeneration / pathology
  • Nerve Tissue Proteins / immunology
  • Nerve Tissue Proteins / physiology*
  • Optic Nerve Injuries / drug therapy*
  • Optic Nerve Injuries / pathology
  • Organ Culture Techniques
  • Protein Binding
  • Rats
  • Rats, Sprague-Dawley
  • Retinal Ganglion Cells / cytology
  • Retinal Ganglion Cells / drug effects*

Substances

  • Antibodies, Neutralizing
  • GPI-Linked Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • RGMA protein, rat
  • Rgma protein, mouse
  • neogenin
  • Caspase 3