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Ruby Shalom-Feuerstein; miR-184 and miR-450b are involved in eye morphogenesis and limbal stem cell differentiation. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):5605.
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The precise dosage of gene expression is essential for correct eye development and limbal stem cell (LSC) differentiation. MicroRNAs (miRNA) are non-coding RNAs that repress gene expression, thereby regulating biological processes. We have previously shown that miR-184 is required for corneal epithelial differentiation of induced pluripotent stem cells (iPSCs) and that miR-450b is a repressor of Pax6, a key regulator of eye development. Here, we examined the involvement of these miRNAs in eye development and LSC differentiation.
The expression pattern of miR-184 and miR-450b was examined in mouse eyes collected at different developmental and post-natal stages, and in human samples of differentiated iPSCs and LSC cultures. The impact of knockdown and overexpression of miR-184 and miR-450b was investigated in mouse embryos grown ex vivo, and in human LSC cultures.
miR450b was initially detected in the lens vesicle following lens placode invagination. Interestingly, spatiotemporal inversed expression of miR-450b and Pax6 was evident in the mouse developing lens. Likewise, in the adult mouse cornea, miR-450b was highly expressed by supra basal corneal epithelial cells but low in Pax6-positive limbus and corneal basal layer cells. In addition, overexpression of miR-450b reduced Pax6 and enhanced differentiation while inhibition of miR-450b showed an opposite effect.<br /> Likewise, miR-184 was elevated in the developing lens and during early LSC differentiation. In the adult cornea, miR-184 was preferentially expressed by corneal progenitors and not by LSCs. The knockdown or over expression of miR-184 resulted in defects in limbal epithelial cell differentiation and stratification. Interestingly, miR-184 directly repressed the stem cell marker cytokeratin 15 and induces early signals of stem cell differentiation.
Our findings suggest that through regulating the dosage of Pax6 protein, miR-450b is effects eye morphogenesis adult corneal epithelial terminal differentiation. Similarly, miR-184 seems to be involved in lens development, while in the adult cornea miR-184 seem to regulate an early step of LSC differentiation, leading to an escape from stemness and/or loss of self-renewal. These data is particularly of interest in line with the fact that point mutation in MIR184 were associated with familiar keratoconus with cataract.
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