title: Retrograde neurotrophic signaling in rat retinal ganglion cells is transmitted via the ERK5 but not the ERK1/2 pathway.
abstract: OBJECTIVE
  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.
authors.affiliation: Department of Ophthalmology, Georg-August-University Hospital, Göttingen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: van Oterendorp
authors.forename: Stavros
authors.initials: S
authors.lastname: Sgouris
authors.forename: Nils
authors.initials: N
authors.lastname: Schallner
authors.forename: Julia
authors.initials: J
authors.lastname: Biermann
authors.forename: Wolf A
authors.initials: WA
authors.lastname: Lagrèze
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D058449:Intravitreal Injections; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D048054:Mitogen-Activated Protein Kinase 7 / Q000378:metabolism*; D009457:Neuroglia / Q000187:drug effects / Q000201:enzymology; D020221:Optic Nerve Injuries; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D012160:Retina / Q000201:enzymology; D012165:Retinal Ganglion Cells / Q000187:drug effects* / Q000201:enzymology; D013477:Superior Colliculi / Q000187:drug effects
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048054:Mitogen-Activated Protein Kinase 7
keywords: extracellular signal-regulated kinase; mitogen-activated protein kinase; optic nerve; rat; retinal ganglion cell