MicroRNA-184 - An Ally in Calcium Signalling in the Skin

The skin provides a protective barrier against environmental, mechanical and microbial assault throughout life. Extracellular calcium (Ca2+) regulates the behavior of keratinocytes, the cells that form the epidermal layer of the skin. Calcium-dependent keratinocyte differentiation has been linked to microRNAs (miRNAs), small non-coding RNA molecules that attenuate gene output through mechanisms that culminate in target mRNA degradation. However, the impact of store-operated calcium entry (SOCE) on keratinocyte miRNA expression has received little attention. Here, I present our recent findings showing a relationship between SOCE and the induction of miRNA-184 (miR-184) in keratinocyte differentiation and migration. Levels of miR-184, barely detectable in untreated cells, rose by about 30-fold after keratinocytes were exposure to 1.5 mM Ca2+ for 5 days. Pharmacologic and genetic inhibitors of SOCE abrogated Ca2+-dependent miR-184 induction by 70%. Further, modulation of miR-184 levels using an exogenous miR-184 mimic or inhibitor enabled us to elucidate roles for miR-184 in keratinocyte differentiation. These include induction of involucrin, an important component of differentiating keratinocytes, elevation of p21 cyclin-dependent kinase (CDK) inhibitor and enhancement of DNA damage, as evidenced by higher levels of γH2AX, a marker of DNA double strand breaks. In addition, I will present our data implicating miR-184 in keratinocyte migration. We observed a 50-fold increase in miR-184 upon wounding keratinocyte monolayers. This occurred under routine low Ca2+ culture conditions, suggesting that high extracellular Ca2+is not an obligatory requirement for SOCE-dependent miR-184 induction. The induction of miR-184 in wounded monolayers was completely abolished in the presence of pharmacologic SOCE inhibitors. Transfection of keratinocytes with a miR-184 mimic stimulated migration in scratch assays, whereas the converse was observed when a miR-184 inhibitor was used. Together, these findings suggest miR-184 functions downstream of SOCE to promote differentiation and migration of epidermal keratinocytes.