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PhD Seminar – Characterization of the role and pathways of microRNA-184 during skin and corneal development and homeostasis

22/08/2019 @ 14:00 - 16:00 IDT

The skin and the cornea are situated at the surface of our body and eye, providing us protection against external insults such as microorganisms, toxicants and physical injury. These tissues share many features including structure, function and common molecular pathways in health and disease. The dynamic replenishment of these tissues depends on very similar epithelial stem cells that give-rise to progenitors that proliferate, differentiate, while migrating towards the tissue surface where they become terminally differentiated and die. Elucidating the molecular circuitry of stem cells and their regulation is required for understanding the etiology of numerous epithelial diseases.

MicroRNAs play a role in various physiological processes including tissue regeneration and diseases. miR-184 is a highly evolutionary conserved microRNA from fly to human. The importance of miR-184 was underscored by the discovery that point mutations in miR-184 gene lead to corneal/lens blinding disease. However, miR-184-related function in vivo remained unclear. Here, we have generated for the first time two mouse models: Mir184 null mice, a model that allows loss-of-function experiment and inducible gain-of-function transgenic (K14-rtTA;Mir184Tg/+) mouse. Mir-184 null mice displayed attenuated differentiation evident by increase in the expression of the stem cell (SC) marker p63 and epidermal hyperplasia linked with increased cell proliferation. In agreement, Mir184-transgenic expression was associated with reduced proliferation, epidermal thinning and premature differentiation. In vitro study has demonstrated that miR-184 activates Notch pathway and differentiation through direct repression of the SC marker K15 and of FIH1. Similar to Notch1 deficient mice, Mir-184-null mice developed larger tumors compare to the wild type mice. Interestingly, Mir184-knockouts displayed corneal stromal thinning and reduced number of stromal cell density, thereby recapitulating some of the phenotypes observed in patients carriers of Mir184 mutation. RNA sequencing followed by in silico analysis revealed a set dysregulated corneal epithelial gene linked with cell adhesion, response to injury, epithelial-stromal crosstalk and keratoconus. In line with defects in basement membrane components in keratoconus, occasional detachment of the corneal epithelium from the underlying stroma were evident in Mir184-null cornea. A drastic reduction in the basement membrane protein Nidogen 1, coincided with diminished expression of the transcription factor Myb, a putative regulator of Nid1 gene. Interestingly, Mir184-null animals delayed wound closure, and enhanced progenitor cell proliferation.

Altogether, we propose that miR-184 induces epidermal differentiation and that it plays a role as a tumor suppressor in the epidermis and by targeting K15 and FIH1, while miss-expression or mutation in miR-184 results in impaired homeostasis. Additionally, we conclude that miR-184 regulates corneal stromal thickness, and corneal epithelial cell commitment, proliferation and adhesion to the basement membrane.


14:00 - 16:00
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