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Christian van Oterendorp, Stavros Sgouris, Nils Schallner, Julia Biermann, Wolf A. Lagrèze; Retrograde Neurotrophic Signaling in Rat Retinal Ganglion Cells Is Transmitted via the ERK5 but Not the ERK1/2 Pathway. Invest. Ophthalmol. Vis. Sci. 2014;55(2):658-665. doi: https://doi.org/10.1167/iovs.13-12985.
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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.
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.
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).
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.
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