Retrograde neurotrophic signaling in rat retinal ganglion cells is transmitted via the ERK5 but not the ERK1/2 pathway

Invest Ophthalmol Vis Sci. 2014 Feb 3;55(2):658-65. doi: 10.1167/iovs.13-12985.


Purpose: Neurotrophic deprivation is considered an important event in glaucomatous retinal ganglion cell (RGC) death. However, the mitogen-activated protein kinase (MAPK) pathway transmitting axonal neurotrophic signals in RGC has not been identified. We investigated the involvement of ERK5 and ERK1/2 in retrograde axonal neurotrophic signaling in rats.

Methods: Adult Sprague-Dawley rats were used. Retinal immunostaining for ERK5 and MEK5 was performed. Levels of total and phosphorylated ERK5 and ERK1/2 were analyzed in retinal lysate by quantitative Western blotting. The effects of age, brain-derived neurotrophic factor (BDNF) stimulation at RGC soma (intravitreal injection) or axon ending (superior colliculus [SC] injection), axonal tyrosine kinase receptor (Trk) receptor inhibition with genistein, and acute axonal damage by optic nerve transection (ONT) were investigated at time points from 24 hours to 5 days.

Results: ERK5 and MEK5 were present in RGCs and glial cells. Phospho-ERK5 levels increased in retina and decreased in brain with age (n = 4; P = 0.039). Phosphorylation of ERK5 but not ERK1/2 was increased or decreased by SC injection of BDNF or genistein, respectively (BDNF at 48 hours [p-ERK5: P = 0.01; p-ERK1/2: P = 0.55, n = 8]; genistein at 48 hours [p-ERK5: P = 0.01; p-ERK1/2: P = 0.5, n = 5]). ONT showed a similar trend. BDNF stimulation at the RGC soma increased both p-ERK5 and p-ERK1/2 (P = 0.035 and P = 0.032, respectively; n = 6; at 48 hours).

Conclusions: ERK5 is present in RGCs. Retina and brain p-ERK5 levels develop differently with age. The response of ERK5 but not ERK1/2 to BDNF stimulation or inhibition at the RGC axon ending indicates that retrograde neurotrophic signals in the rat optic nerve may be mediated by the ERK5 pathway.

Keywords: extracellular signal-regulated kinase; mitogen-activated protein kinase; optic nerve; rat; retinal ganglion cell.

MeSH terms

  • Aging / physiology
  • Animals
  • Blotting, Western
  • Brain / enzymology
  • Brain-Derived Neurotrophic Factor / pharmacology*
  • Intravitreal Injections
  • MAP Kinase Signaling System / physiology*
  • Male
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mitogen-Activated Protein Kinase 7 / metabolism*
  • Neuroglia / drug effects
  • Neuroglia / enzymology
  • Optic Nerve Injuries
  • Phosphorylation
  • Rats
  • Rats, Sprague-Dawley
  • Retina / enzymology
  • Retinal Ganglion Cells / drug effects*
  • Retinal Ganglion Cells / enzymology
  • Superior Colliculi / drug effects


  • Brain-Derived Neurotrophic Factor
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinase 7