Skin pigmentation is the result from both overproduction and uneven distribution of melanin during aging. Vertical distribution of melanin in epidermis is regulated by keratinocytes' turnover, yet factors involved in horizontal distribution have seldom reported. Horizontal distribution of melanin is thought be affected by melanocytes migration because melanocytes localize on the basement membrane. DENN domain containing 1A (DENND1A) is a member of the connecdenn family and is involved in epidermal growth factor-promoted cell migration by regulating clathrin-mediated endocytosis. Although the relationship between DENND1A and the pathology in ovaries or uterus has been studied, the role of DENND1A in the skin is still unknown. The aims of this study were to investigate the role of DENND1A in melanocytes migration and influence to age-related melanin accumulation by intrinsic- and extrinsic-aging. As a result, DENND1A knocked-down melanocytes using siRNA techniques showed cell aggregation and formed spheroid, indicating that DENND1A regulated cell to cell adhesion. Gene expression of adhesion molecules CDH11, CDH19 and CLDN11 was upregulated in melanocytes with DENND1A knocked-down. Additionally, melanin production increased in DENND1A knocked-down melanocytes. For investigating the role of DENND1A in age-related melanin accumulation, DENND1A expression in melanocytes was determined in several culture conditions. The result showed that decreased expression of DENND1A in passaged cells. Furthermore, both exposure to Ultraviolet B and hydrogen peroxide downregulated DENND1A expression, respectively. These results indicated that DENND1A decreased in both intrinsic- and extrinsic-aged melanocytes. This study presented that DENND1A decrease in melanocytes induced aggregation of melanocytes and melanogenesis, and that aging simulated-culture condition decreased DENND1A expression, suggesting DENND1A should be a novel target for controlling skin pigmentation in aged skin.

Downregulation of DENND1A accelerates spheroid formation through increasing gene expression of adhesion molecules in cultured melanocytes