Loss of Extracellular Signal-Regulated Kinase 1/2 in the Retinal Pigment Epithelium Leads to RPE65 Decrease and Retinal Degeneration.
Aswin PyakurelDelphine BalmerMarc K Saba-El-LeilCaroline KizilyaprakJean DaraspeBruno M HumbelLaure VoisinYun Z LeJohannes von LintigSylvain MelocheRaphaël RoduitPublished in: Molecular and cellular biology (2017)
Recent work suggested that the activity of extracellular signal-regulated kinase 1/2 (ERK1/2) is increased in the retinal pigment epithelium (RPE) of age-related macular degeneration (ARMD) patients and therefore could be an attractive therapeutic target. Notably, ERK1/2 pathway inhibitors are used in cancer therapy, with severe and noncharacterized ocular side effects. To decipher the role of ERK1/2 in RPE cells, we conditionally disrupted the Erk1 and Erk2 genes in mouse RPE. The loss of ERK1/2 activity resulted in a significant decrease in the level of RPE65 expression, a decrease in ocular retinoid levels concomitant with low visual function, and a rapid disorganization of RPE cells, ultimately leading to retinal degeneration. Our results identify the ERK1/2 pathway as a direct regulator of the visual cycle and a critical component of the viability of RPE and photoreceptor cells. Moreover, our results caution about the need for a very fine adjustment of kinase inhibition in cancer or ARMD treatment in order to avoid ocular side effects.
Keyphrases
- signaling pathway
- induced apoptosis
- pi k akt
- cell cycle arrest
- cell proliferation
- transcription factor
- cancer therapy
- age related macular degeneration
- optical coherence tomography
- optic nerve
- ejection fraction
- newly diagnosed
- early onset
- end stage renal disease
- drug delivery
- protein kinase
- prognostic factors
- genome wide
- dna methylation
- functional connectivity
- resting state