Melanocyte Development and Pigmentation Signaling

Melanocytes are the cells responsible for skin, hair, and eye color. Melanocytes reside at the junction of the dermis and the epidermis. They are well known for their ability to produce and distribute melanin. Melanin is produced in melanosomes, specialized organelles that are translocated from the center of melanocyte cytoplasm to the tip of its dendrites. In animals there are two major classes of natural melanins, the black-brown eumelanin and the yellow-red pheomelanin. Melanocytic development and pigmentation is regulated in large part by the bHLH-Lz microphthalmia-associated transcription factor (MITF). MITF activity is controlled by at least two signaling pathways: MSH and Kit signaling pathways.The effects of α-MSH on melanogenesis are mediated via MC1R and tyrosinase. α-MSH is produced together with several other peptides, by the proteolytic cleavage of the large precursor protein Pro-Opiomelanocortin (POMC). On binding to MC1R, α-MSH activates AC, which, in turn, causes an increase in intracellular cAMP. cAMP activates PKA, which phosphorylates and activates CREB. CREB then binds to the CRE domain present in the MITF promoter, thereby upregulating its transcription. Thus, MSH stimulation profoundly increases MITF protein expression over the course of hours. cAMP also increases the binding affinity of MITF to the E-box and its binding to the M-box present in the promoters of genes encoding melanogenic enzymes. Increase in cAMP also results in the activation of tyrosinase, the rate-limiting enzyme in the melanin pathway. Other α-MSH-related melanocortin peptides, such as ACTH1-17 and deacetylated α-MSH are also agonists at the MC1R and could regulate melanocyte function.Kit signaling up-regulates MITF function through MAPK phosphorylation of MITF. Kit is activated by binding to its ligand SCF. SCF binds to the c-KIT receptor on melanocytes, thus mediating dimerization, activation of its intrinsic tyrosine kinase activity, and autophosphorylation. The activated c-KIT receptor then phosphorylates various substrates and associates with various signaling molecules including SHC and GRB2 adaptor proteins and the guanine nucleotide exchange factor SOS, all of which lead to activation of the Ras-MAPK pathway. MAPK may directly activate MITF or it may activate p90RSK1. Activated MITF pairs with the co-activator p300. Once MITF is paired, it turns on the anti apoptotic Bcl2, among other genes. MITF phosphorylation also couples transactivation to proteasome mediated degradation. Kit signaling thus triggers short lived MITF activation and net MITF degradation.MITF role in differentiation pathways has been highlighted by its potent transcriptional and lineage specific regulation of the three major pigment enzymes: tyrosinase, TRP1/TyrpI and TRP2/Dct as well as other pigmentation factors. The transcription factors Pax3, Sox10, and LEF1 transactivate the MITF gene promoter and play important roles in melanocytic lineage development. The paired homeodomain factor Pax3 can regulate the Tyrp1 promoter. The HMG box protein Sox10 binds the proximal MITF-M promoter as well as an upstream enhancer and can cooperate with, although not interact with, MITF in activation of the Dct promoter. MITF is involved in survival pathways during normal development as well as during neoplastic growth of melanoma. Besides producing melanin, melanocytes have other physiological significance. They act as local stress sensors in the epidermis and provide communicatory links with several different systems. They are a key component of a communication pathway between the skin and the central nervous system.