The Pinkeyed‐Dilution Protein and the Eumelanin/Pheomelanin Switch: In Support of a Unifying Hypothesis

Abstract

The two major types of mammalian melanin are pheomelanin (yellow or red pigment) and eumelanin (black or brown). The agouti (A) and extension (E) loci determine whether follicular melanocytes will deposit pheomelanin or eumelanin within their melanosomes. Mutations at the murine pinkeyed-dilution (P) locus cause a striking reduction in deposition of eumelanic, but not pheomelanic, pigment. The mRNA encoded at the P locus is not expressed in skin that exclusively produces pheomelanic pigment as a result of mutation at the agouti locus. We have suggested, based upon both genetic and biochemical evidence, that three key melanogenic proteins--tyrosinase, tyrosinase-related-protein-1 (TRP-1), and TRP-2, encoded at the albino (C), brown (B), and slaty (Slt) loci, respectively--form a high-molecular-weight "melanogenic complex" within the melanosome. High-molecular-weight forms of tyrosinase, TRP-1 and TRP-2, are absent from eumelanic ocular tissues of p(un)/p(un) mice that fail to produce normal P-locus transcript, even though these mice are genetically normal at the loci that regulate production of the three melanogenic proteins. We have hypothesized that the presence of the p-locus protein is important for the integrity of the melanogenic complex and for the levels of members of the TRP family. We show here that the yellow skins of mice mutant at the agouti or extension loci, as well as the nonyellow skins of pinkeyed-unstable (p(un)/p(un)) mice, demonstrate greatly diminished levels of tyrosinase, TRP-1 and TRP-2, and an absence or markedly decreased proportion of high-molecular-weight forms of melanogenic proteins. We conclude that normal levels of wild-type P-locus protein are necessary for eumelanogenesis and that the absence of this protein may be necessary, but is not sufficient to cause the melanosome to switch to the production of pheomelanin. We discuss the implications of our results in relation to the interacting genetic controls regulating melanogenesis.

Characterization of genes modulated during pheomelanogenesis using differential display

“…Transient expression of ASP from days 4-6 of the hair growth cycle switches follicular melanocytes to the production of pheomelanin rather than eumelanin; after that, agouti gene expression is turned off, and eumelanin is produced again. Analyses of protein and mRNA expression during such hair growth have shown that tyrosinase-related protein (TRP) 1, TRP2, Pmel17͞silver, and the protein encoded at the pinkeyed-dilution locus are completely suppressed during pheomelanogenesis, whereas expression of tyrosinase is reduced but not eliminated (9,10). This pattern of expression is consistent with the fact that tyrosinase is required for both types of pigment synthesis, but expression of these other melanogenic proteins is required only for eumelanin synthesis.…”

Gene–gene interactions contribute to eye colour variation in humans

“…The obtained results confirmed the predominant role in eye colour inheritance of two genes located on chromosome 15; that is, HERC2 and OCA2. The OCA2 gene encodes a protein that is an integral part of the melanosomal membrane and is responsible for regulation of pH inside the melanosome, [55][56][57] which, in consequence, has an influence on the activity of the enzyme tyrosinase, which has a crucial role in the synthesis of the pigment melanin. The important role of OCA2 in eye colour determination was confirmed in many studies, 11,13,28,31,[58][59][60][61] and further investigations revealed that regulation of OCA2 expression through the neighbouring HERC2 gene might have a crucial role.…”

Digital gene expression for non-model organisms

“…Tyrp1, Dct, and Pmel encode melanogenic genes and are well-known targets of Mc1r based on studies of cultured melanocytes (Kobayashi et al 1995;Lamoreux et al 1995), but an effect of Mc1r on Brca2 and Smug1 has not been described previously and may contribute to differences in skin cancer susceptibility. We also note that Slc7a11, which encodes a melanocyte-specific cystine transporter that is essential for pheomelanin (yellow pigment) synthesis (and in which a loss-of-function is responsible for the subtle gray coat color mutation), is up-regulated (19.2 TPM in Mc1r +/+ vs. 44.5 TPM in Mc1r e/e skin), which supports a hypothesis based on biochemical studies that cystine transport plays an instructive role in pigment-type switching (Chintala et al 2005;Simon et al 2009).…”

“…Studies of additional cheetah samples will a Expression levels are given as tags per million reads of an EDGE library prepared from RNA of a black spot or yellow background area of cheetah skin. The genes shown here were chosen based on their roles in pigment cell biology; six are well-established melanocyte transcriptional targets downstream from MC1R signaling (Kobayashi et al 1995;Lamoreux et al 1995;Chintala et al 2005;April and Barsh 2006;Le Pape et al 2009); four encode secreted factors that act upstream, either as ligands or to modify ligands of the MC1R Enshell-Seijffers et al 2008;Kaelin et al 2008); and one, MITF, encodes a transcription factor required for melanocyte development (Steingrímsson et al 2006). The expected direction, increase (+) or decrease (À), for expression level change of each gene is given according to when pigment production switches from yellow pheomelanin to black eumelanin.…”