Melanocyte Development and Pigmentation
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Melanocyte Development and Pigmentation
Human Skin is made up of two main layers, the Epidermis, which is described as a Stratified Squamous Epithelium mainly consisting of Keratinocytes, and the Dermis, an underlying layer of Vascularized Connective Tissue. Melanocytes reside at the junction of the Dermis and the Epidermis. Mature Melanocytes form long Dendritic processes that ramify among the neighboring Keratinocytes. Melanocytes are well known for their role in Skin pigmentation, and their ability to produce and distribute Melanin has been studied extensively. Melanin is produced in Melanosomes, specialized organelles that are translocated from the center of the Melanocyte cytoplasm to the tip of its Dendrites. The Dendrites are then involved in the transfer of the Melanosomes to the Keratinocytes. In Animals there are two major classes of natural Melanins, the black-brown Eumelanin found in Human black hair and in the Retina of the eye and the yellow-red Pheomelanin found in red hair and red feathers. The Melanocytic Development and Pigmentation is regulated in large part by the bHLH-Lz MITF (Microphthalmia-associated Transcription Factor). MITF activity is controlled by at least two signaling pathways: MSH (Melanocyte-Stimulating Hormone) and Kit (v-Kit Hardy-Zuckerman 4 Feline Sarcoma Viral Oncogene Homolog) signaling pathways (Ref.1).

The effects of Alpha-MSH on Melanogenesis are mediated via the MC1R (Melanocortin-1 Receptor) and Tyrosinase, the rate-limiting enzyme in the Melanogenesis pathway. Alpha-MSH is produced, together with several other peptides, by the proteolytic cleavage of the large precursor protein POMC (Pro-Opiomelanocortin). On binding to the MC1R, Alpha-MSH activates ADCY (Adenylate Cyclase), which, in turn, causes an increase in intracellular cAMP (Cyclic Adenosine Monophosphate). cAMP activates cAMP-dependent PKA (Protein Kinase-A). PKA phosphorylates and activates CREB (cAMP Response Element-Binding Protein) which, when activated, binds to the CRE (cAMP response element) domain present in the Microphthalmia promoter, thereby upregulating its transcription. Thus, MSH stimulation profoundly increases MITF protein expression over the course of hours. In addition to the transcriptional up-regulation of MITF expression through the cAMP-responsive element, cAMP also increases the binding affinity of MITF to the E-box (a CAXXTG motif) and, to a greater extent, its binding to the M-box (a CATGTG motif) present in the promoters of genes encoding Melanogenic enzymes. This is the classical pathway by which Alpha-MSH is believed to mediate its Melanogenic effects on Melanocytes. Increases in cAMP result, via PKA, in the activation of Tyrosinase, the rate-limiting enzyme in the Melanin pathway. Evidence suggests that Alpha-MSH increases the expression, de novo synthesis, and activation of Tyrosinase. Other Alpha-MSH-related Melanocortin peptides, such as ACTH1-17 and desacetylated Alpha-MSH, are also agonists at the MC1R and could regulate Melanocyte function (Ref.2).

Kit signaling up-regulates MITF function through MAP kinase phosphorylation of MITF, thereby recruiting the p300 transcriptional coactivator. Kit signaling triggers two phosphorylation events on MITF, which up-regulate transactivation potential yet simultaneously target MITF for ubiquitin-dependent proteolysis. Kit is activated by binding to its ligand KitL (Kit-ligand) also known as steel factor, Stem Cell Factor and Mast Cell Growth Factor. SCF (Stem Cell Factor), works via cellular messengers Kit and MAPK. MAPK may directly activate MITF or it may activate p90RSK1 (Ribosomal-S6 Kinase-1). Activated MITF pair with the co-activator p300. Once MITF is paired, it turns on the anti-apoptotic Bcl2 (B-Cell CLL/Lymphoma-2), among other genes. MITF phosphorylations may also couple transactivation to proteasome-mediated degradation. Kit signaling thus triggers short-lived MITF activation and net MITF degradation, in contrast to the profoundly increased MITF expression after MSH signaling, potentially explaining the functional diversity of this transcription factor in regulating proliferation, survival, and differentiation in Melanocytes (Ref.3).

Several promoters that specify expression patterns control the expression of mouse and human MITF. The best characterized is the MITF-M promoter that is essential for MITF expression in the neural crest-derived Melanocyte population. 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 (Tyrosinase-Related Protein-1) and TRP2/Dct (Tyrosinase-Related Protein-2) as well as other pigmentation factors. The transcription factors Pax3, Sox10, and LEF1 ((Lymphoid Enhancer Factor-1) 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 (Dopachrome Tautomerase) promoter. The LEF1/TCF (Lymphoid Enhancer Factor/T-Cell Factor) family of transcription factors that interact with Beta-Catenin enable MITF expression to be regulated by WNT (Wingless-Type MMTV Integration Site Family Member-1) signaling (Ref.4). The regulation of the MITF promoter by WNT signaling via a LEF1/TCF binding site most likely explains why over-expression of components of the WNT signaling pathway promotes an increase in the numbers of Melanoblasts in the neural crest. MITF is involved in survival pathways during normal development as well as during neoplastic growth of Melanoma. Nevertheless, it appears that Melanocytes are not simply Melanin-producing cells and may have some other physiological significance. It has been proposed that Melanocytes act as local "stress sensors" in the epidermis and provide communicatory links with several different systems. For example, their close anatomic associations with nerve endings and their ability to produce neuropeptides and neurotransmitters suggest a role as a neuroendocrine cell and thus as a key component of a communication pathway between the skin and the central nervous system (Ref.5).