Changes in the Proliferation and Differentiation of Neonatal Mouse Pink‐Eyed Dilution Melanocytes in the Presence of Excess Tyrosine

Abstract

Changes in the proliferation and differentiation of epidermal melanocytes derived from newborn mice wild-type at the pink-eyed dilution (p) locus (P/P) and from congenic mice mutant at that locus (p/p) were investigated in serum-free primary culture, with or without the addition of L-Tyr. Incubation with added L-Tyr inhibited the proliferation of P/P melanocytes in a concentration-dependent manner and inhibition was gradually augmented as the donor mice aged. In contrast, L-Tyr stimulated the proliferation of p/p melanoblasts-melanocytes derived from 0.5-day-old mice, but inhibited their proliferation when derived from 3.5- or 7.5-day-old mice. L-Tyr stimulated the differentiation of P/P melanocytes. However, almost all cells were undifferentiated melanoblasts in control cultures derived from 0.5-, 3.5- and 7.5-day-old p/p mice, but L-Tyr induced their differentiation as the age of the donor mice advanced. The content of the eumelanin marker, pyrrole-2,3,5-tricarboxylic acid as well as the pheomelanin marker, 4-amino-3-hydroxyphenylalanine in p/p melanocytes was greatly reduced compared with P/P melanocytes. However, the contents of eumelanin and its precursor, 5,6-dihydroxyindole-2-carboxylic acid, as well as the contents of pheomelanin and its precursor, 5-S-cysteinyldopa in culture media from p/p melanocytes were similar to those of P/P melanocytes at all ages tested. L-Tyr increased the content of eumelanin and pheomelanin two- to threefold in cultured cells and media derived from 0.5-, 3.5- and 7.5-day-old mice. These results suggest that the proliferation of p/p melanoblasts-melanocytes is stimulated by L-Tyr, and that the differentiation of melanocytes is induced by L-Tyr as the age of the donor mice advanced, although eumelanin and pheomelanin fail to accumulate in p/p melanocytes and are released from them at all ages of skin development.

High levels of melanin‐related metabolites in plasma from pink‐eyed dilution mice

“…, 2003). The dramatic increases in the plasma levels of 6H5MI2C and 5‐ S ‐CD after birth are also consistent with our previous results on the p/p melanocytes (Hirobe et al. , 2003).…”

“…, 2007). The mouse pink‐eyed dilution ( p ) locus greatly reduces the production of eumelanin in melanocytes and in the retinal pigment epithelium (Hirobe et al. , 2003).…”

“…Pigmentation is switched from the production of eumelanin to pheomelanin in recessive yellow (e/e) mice, which are homozygous for a loss-of-function mutation at the extension (E) locus (Hirobe et al, 2007). The mouse pink-eyed dilution (p) locus greatly reduces the production of eumelanin in melanocytes and in the retinal pigment epithelium (Hirobe et al, 2003). The product of the p gene is an integral membrane protein that localizes in melanosomes.…”

L‐tyrosine and L‐dihydroxyphenylalanine as hormone‐like regulators of melanocyte functions

“…Also studies on melanoblasts and melanocytes from C57BL/10 mice demonstrated that L‐tyrosine also increases formation of premelanosomes and melanosomes in mutant (pp) melanocytes and increased intracellular concentration of c‐Kit, TyrP1 and TyrP2 protein in both non‐mutant (PP) and pp cells with increased tyrosinase accumulation, as demonstrated by DOPA cytochemistry (Hirobe et al., 2002). Interestingly, L‐tyrosine, while stimulating proliferation of pp melanocytes inhibited growth of PP melanocytes (Hirobe et al., 2003). Furthermore, Hirobe et al.…”

Melanocyte Pygmentation – Friend or Foe on the Route to Melanoma

“…Also, the synthesis of pheomelanin, consumes cysteine and this may further limit the capacity of the cellular antioxidative defense (Smith et al, 2008). In fact, in cultured normal melanocytes, stimulation of melanogenesis leads to the suppression of proliferation, cell senescence and eventually to cell death (Hirobe et al, 2003). Melanogenesis process generates highly toxic melanin intermediates and byproducts.…”