Skin aging is a complex biological process leading to multiple functional defects in the different structure of the skin tissues. Epidermal aging is especially characterized by an alteration of the tissue renewal associated to an impairment of the keratinocytes differentiation process. We have previously reported that the microRNA miR-30a is over-expressed in aged epidermis and we have shown in organotypic skin models that this induction impairs epidermal differentiation, induces cell apoptosis, increases oxidative stress and leads to strong defects of the epidermal barrier function. MiR-30a appears therefore as a key regulator of epidermal aging. However, the mechanisms modulating miR-30a expression, especially during skin aging, need to be clarified. We hypothesized that the NOTCH signaling pathway could play a role in miR-30a regulation since a miR30a-MYC-NOTCH regulatory loop has been previously described in cancer cells. To clarify this regulation in human epidermis, we used a reporter system of miR-30a activity in cultured keratinocytes treated by NOTCH chemical inhibitors. We clearly observed that impairment of NOTCH signaling activates miR-30a expression in cultured keratinocytes, independently to MYC expression. We then investigated NOTCH activity in young vs aged samples of human skin. By immunofluorescence of the NOTCH1 receptor and its intracellular part NICD, we found a significant inverse correlation between the age of the patients and the NOTCH1 receptor expression. Finally, we identified a putative binding site for the transcriptional NOTCH effector RBPJ in the promoter sequence of miR-30a. Preliminary ChIP data indicates that RBPJ could directly binds miR-30a promoter. Altogether, our data reveal that the impairment of the NOTCH signaling pathway in aged skin contributes to miR-30a activation. These results open the way to potential strategies aiming at controlling miR-30a expression during skin aging.

ESDR190 - Down-regulation of the NOTCH pathway during skin aging contributes to functional epidermal defects through miR-30a activation

The scientific meeting of the European Society for Dermatological Research (ESDR) is held yearly, usually in September. With an international attendance of more than 1000 skin scientists from around the globe, the four-day event includes short oral presentations from peer-reviewed abstracts, keynote lectures from international experts, sponsored symposia, satellite programs, educational events as well as an important focus on posters, networking and building collaborations amongst scientists. For more information about this year’s meeting visit our website.