June 2015
Volume 56, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2015
miR-184 and miR-450b are involved in eye morphogenesis and limbal stem cell differentiation
Author Affiliations & Notes
  • Ruby Shalom-Feuerstein
    Genetics & Developmental Biology, Technion - Israel Institute of Technology, Haifa, Israel
  • Footnotes
    Commercial Relationships Ruby Shalom-Feuerstein, None
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    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 5605. doi:
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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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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: 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.

Methods: 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.

Results: 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.

Conclusions: 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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