microRNAs in the Regulation of Melanogenesis

Abstract

Melanogenesis is the process leading to the synthesis of melanin, the main substance that influences skin color and plays a pivotal role against UV damage. Altered melanogenesis is observed in several pigmentation disorders. Melanogenesis occurs in specialized cells called melanocytes, physically and functionally related by means of autocrine and paracrine interplay to other skin cell types. Several external and internal factors control melanin biosynthesis and operate through different intracellular signaling pathways, which finally leads to the regulation of microphthalmia-associated transcription factor (MITF), the key transcription factor involved in melanogenesis and the expression of the main melanogenic enzymes, including TYR, TYRP-1, and TYRP-2. Epigenetic factors, including microRNAs (miRNAs), are involved in melanogenesis regulation. miRNAs are small, single-stranded, non-coding RNAs, of approximately 22 nucleotides in length, which control cell behavior by regulating gene expression, mainly by binding the 3' untranslated region (3'-UTR) of target mRNAs. This review collects data on the miRNAs involved in melanogenesis and how these miRNAs can modulate target gene expression. Bringing to light the biological function of miRNAs could lead to a wider understanding of epigenetic melanogenesis regulation and its dysregulation. This knowledge may constitute the basis for developing innovative treatment approaches for pigmentation dysregulation.

Keywords: melanocyte; melanogenesis; microRNA; skin pigmentation.

Figure 1

Representation of the melanogenic unit and melanin synthesis in melanosomes (left). Schematic representation of eumelanin and pheomelanin biosynthetic pathways (right).

Figure 2

Main signaling pathways involved in melanogenesis regulation. α-melanocyte stimulating hormone (α-MSH) binds to melanocortin 1 receptor (MC1R), which increases cAMP levels, activating PKA and PI3K/AKT pathway. The former phosphorylates CREB protein, promoting MITF transcription; the latter interplays with Wnt/β-catenin pathway by phosphorylating GSK-3β, which, in turn, releases β-catenin to promote MITF transcription. Stem cell factor (SCF) binds to c-KIT receptor, activating MAPK pathway and phosphorylating CREB. Peptide endothelin 1 (ET-1) binds to its receptor, ETRB, activating PKC and stimulating MITF transcription. MITF is phosphorylated at the post-transcriptional level to promote transcription of the melanogenic enzymes.