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K. Bharti, M. Gasper, M. Brucato, A. Maminishkis, S. S. Miller, H. Arnheiter; PAX6 and MITF Play a Dose-Dependent Role in Determining Cell Fate of the Retinal Pigment Epithelium (RPE) and Putative Ocular Stem Cells. Invest. Ophthalmol. Vis. Sci. 2010;51(13):1235.
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© ARVO (1962-2015); The Authors (2016-present)
Previous observations in mice with mutations in the bHLH-zipper transcription factor MITF suggested a potential role for increased levels of the paired/homeodomain transcription factor PAX6 in regulating dorsal-restricted RPE-retina transdifferentiation. Therefore, we evaluated the role of Pax6 gene dose in the RPE and the ciliary epithelium (CE).
Histological and molecular evaluation of RPE-retina transdifferentiation in mice harboring a combination of different Mitf and Pax6 alleles.
A reduction of Pax6 gene dose in an Mitf mutant background markedly enhances the hyperproliferation and dorsal-restricted RPE-retina transdifferentiation observed with Mitf mutations alone. Conversely, an increase in Pax6 gene dose decreases Mitf-mutation mediated hyperproliferation and transdifferentiation. This regulation of RPE proliferation by Pax6 and Mitf is concomitant with an increase in levels of alpha B crystallin which, based on studies in other cell types, decreases Cyclin D1 protein stability through the ubiquitin ligase SCFFBX4 and so inhibits the cell cycle. Moreover, PAX6 positively regulates TFEC, an MITF homolog, which, like MITF, is thought to promote RPE development and inhibit retinogenic gene expression in the RPE. In postnatal CE, high PAX6 levels expand a pool of putative stem cells while low PAX6 levels, in conjunction with Mitf mutations, decrease this pool and increase a pool of cells expressing retinal progenitor markers.
In the Mitf mutant RPE, a decrease in Pax6 gene dose leads to an increase in retinal gene expression, and an increase in Pax6 gene dose to a decrease in retinal gene expression. Consistent with this, in the postnatal CE, PAX6 levels regulate the balance between putative stem cells and retinal progenitor cells. Thus, in both the developing RPE and the postnatal CE, the coordinate reduction in PAX6 and MITF activities helps to initiate the transition of cells towards a neuroretinal fate while an increase in PAX6 and MITF/TFEC activities has antiretinogenic effects.
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