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Natalie Wolkow, Arvydas Maminishkis, Jared Iacovelli, Jennifer Lee, Sheldon Miller, Joshua Dunaief; Iron Upregulates Melanogenesis Genes in the RPE. Invest. Ophthalmol. Vis. Sci. 2013;54(15):6071.
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The purpose of our study was to examine the effects of iron on melanogenesis in human fetal RPE cells. Our prior studies on retinas from mice and humans with altered iron transport suggested that increased iron may influence the cellular pathways used for melanosome biogenesis and degradation in RPE cells.
Human Fetal RPE cells were treated with 250µM ferric ammonium citrate for one week. RNA was extracted using the QIAGEN RNeasy Mini Kit. Reverse transcription and quantitative PCR were performed using Taqman reagents and Taqman probes.
Human fetal RPE cells that were treated with ferric ammonium citrate for 1 week had significantly increased RNA expression levels of Tyrosinase (1.5-fold, p<0.05), Tyrosinase-related protein 1 (1.5-fold, p<0.05) and Hermansky-Pudlak Syndrome 3 (1.4-fold, p<0.01) genes; however, the RNA expression level of the melanosome structural protein, Premelanosome protein (PMEL), was not increased. Additionally, the RNA expression level of Microphthalmia associated transcription factor (MITF), which is an upstream regulator of all the aforementioned genes, was upregulated 1.6-fold (p<0.001). Several pathways converge on MITF to cause MITF upregulation. Of the known regulators of MITF expression, SRY-box 9 (Sox 9) and SRY-box 10 (Sox 10) RNA expression levels were upregulated after iron treatment, Sox 9 was upregulated 1.6-fold (p<0.05) and Sox 10 was upregulated 1.4-fold (p<0.01).
Human fetal RPE cells upregulate several genes that are important for melanogenesis after exposure to ferric ammonium citrate. The upregulation of these melanogenesis genes likely occurs via the Sox 9 and Sox 10 pathways of MITF activation. Since melanosomes can bind iron and, up to a point, protect cells from its deleterious effects, iron-induced melanogenesis may be cytoprotective.
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