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

Wakamatsu, Kazumasa; Hirobe, Tomohisa; Ito, Shosuke

doi:10.1111/j.1600-0749.2007.00370.x

Cited by 13 publications

(7 citation statements)

References 16 publications

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“…A kinetic study showed that pheomelanogenesis is kinetically favored under more acidic conditions because the cyclization of dopaquinone (the first step in eumelanogenesis) proceeds much more slowly at low pH, whereas the cysteinyldopaquinone cyclization (yielding the first bicyclic intermediate in pheomelanogenesis) proceeds more quickly (Simon et al., 2009; Thompson et al., 1985). In pink‐eyed dilution melanocytes, melanin precursors may be released from melanosomes due to their acidity and circulate in the form of 6‐hydroxy‐5‐methoxyindole‐2‐carboxylic acid, a eumelanin‐related metabolite, and 5‐ S ‐cysteinyldopa, a pheomelanin precursor (Wakamatsu et al., 2007).…”

Section: Discussionmentioning

confidence: 99%

“…The proliferation and differentiation of neonatal mouse epidermal melanocytes in culture are greatly inhibited by the p mutation (Hirobe et al., 2002a). Excess l ‐tyrosine (Tyr) added to culture medium rescues both proliferation and differentiation of p/p melanocytes (Hirobe et al., 2002b), although most of the melanin as well as its precursors failed to accumulate in p/p melanocytes and was released from them (Hirobe et al., 2003; Wakamatsu et al., 2007). Moreover, in p/p melanoblasts, only a few stage I and II melanosomes were observed, whereas in p/p melanocytes treated with l ‐Tyr, the number of stage II and III melanosomes increased dramatically (Hirobe et al., 2002b).…”

Section: Introductionmentioning

confidence: 99%

“…In addition to the frameshift mutation, the Mc1r e allele has a conserved point mutation, Val101Ala (Robbins et al., 1993). The Mc1r e gene stimulates pheomelanin synthesis in the epidermis and dermis as well as the hair follicle (Hirobe et al., 2007a), and a higher level of pheomelanin precursor, 5‐ S ‐cysteinyldopa, was observed in plasma (Wakamatsu et al., 2007). Furthermore, there were higher levels of eumelanin and pheomelanin in dorsal hairs of female Mc1r e /Mc1r e mice 5 weeks after birth than in dorsal hairs of male mice (Hirobe et al., 2007b).…”

Section: Introductionmentioning

confidence: 99%

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The mouse pink‐eyed dilution allele of the P‐gene greatly inhibits eumelanin but not pheomelanin synthesis

Hirobe¹,

Ito

Wakamatsu

2010

Pigment Cell Melanoma Res

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The mouse pink-eyed dilution (p) locus is known to control eumelanin synthesis, melanosome morphology, and tyrosinase activity in melanocytes. However, it has not been fully determined whether the mutant allele, p affects pheomelanin synthesis. Effects of the p allele on eumelanin and phemelanin synthesis were investigated by chemical analysis of dorsal hairs of 5-week-old mice obtained from the F(2) generations (black, pink-eyed black, recessive yellow, pink-eyed recessive yellow, agouti, and pink-eyed agouti) between C57BL/10JHir (B10)-congenic pink-eyed black mice (B10-p/p) and recessive yellow (B10-Mc1r(e)/Mc1r(e)) or agouti (B10-A/A) mice. The eumelanin content was dramatically (>20-fold) decreased in pink-eyed black and pink-eyed agouti mice, whereas the pheomelanin content did not decrease in pink-eyed black, pink-eyed recessive yellow, or pink-eyed agouti mice compared to the corresponding P/- mice. These results suggest that the pink-eyed dilution allele greatly inhibits eumelanin synthesis, but not pheomelanin synthesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The mouse pink‐eyed dilution allele of the P‐gene greatly inhibits eumelanin but not pheomelanin synthesis

Hirobe¹,

Ito

Wakamatsu

2010

Pigment Cell Melanoma Res

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“…This results in protein cleavage and secretion of active tyrosinase and melanin. As a result, mice bearing the p-mutation show higher circulating levels of pigment precursors such as 5- S -cysteinyldopa (5- S -CD) and dihydroxyindolecarboxylic (DHICA) acid than fully pigmented animals [13].…”

Section: Introductionmentioning

confidence: 99%

The Classical Pink-Eyed Dilution Mutation Affects Angiogenic Responsiveness

et al. 2012

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Angiogenesis is the process by which new blood vessels are formed from existing vessels. Mammalian populations, including humans and mice, harbor genetic variations that alter angiogenesis. Angiogenesis-regulating gene variants can result in increased susceptibility to multiple angiogenesis-dependent diseases in humans. Our efforts to dissect the complexity of the genetic diversity that regulates angiogenesis have used laboratory animals due to the availability of genome sequence for many species and the ability to perform high volume controlled breeding. Using the murine corneal micropocket assay, we have observed more than ten-fold difference in angiogenic responsiveness among various mouse strains. This degree of difference is observed with either bFGF or VEGF induced corneal neovascularization. Ongoing mapping studies have identified multiple loci that affect angiogenic responsiveness in several mouse models. In this study, we used F2 intercrosses between C57BL/6J and the 129 substrains 129P1/ReJ and 129P3/J, as well as the SJL/J strain, where we have identified new QTLs that affect angiogenic responsiveness. In the case of AngFq5, on chromosome 7, congenic animals were used to confirm the existence of this locus and subcongenic animals, combined with a haplotype-based mapping approach that identified the pink-eyed dilution mutation as a candidate polymorphism to explain AngFq5. The ability of mutations in the pink-eyed dilution gene to affect angiogenic response was demonstrated using the p-J allele at the same locus. Using this allele, we demonstrate that pink-eyed dilution mutations in Oca2 can affect both bFGF and VEGF-induced corneal angiogenesis.

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“…(1998). Also, pink‐eyed dilution mice secrete high levels of melanin‐related metabolites, such as 5‐ S ‐cysteinyldopa, into the blood compared to wild‐type mice (Wakamatsu et al., 2007). Thus, it seems likely that the p mutation causes a defect in retaining melanin and melanin precursors in melanosomes.…”

Section: Effects Of Mutations On Mouse/human Pigmentationmentioning

confidence: 99%

Human hair melanins: what we have learned and have not learned from mouse coat color pigmentation

Ito

Wakamatsu

2011

Pigment Cell Melanoma Res

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125

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Hair pigmentation is one of the most conspicuous phenotypes in humans. Melanocytes produce two distinct types of melanin pigment: brown to black, indolic eumelanin and yellow to reddish brown, sulfur-containing pheomelanin. Biochemically, the precursor tyrosine and the key enzyme tyrosinase and the tyrosinase-related proteins are involved in eumelanogenesis, while only the additional presence of cysteine is necessary for pheomelanogenesis. Other important proteins involved in melanogenesis include P protein, MATP protein, α-MSH, agouti signaling protein (ASIP), MC1R (the receptor for MSH and ASIP), and SLC7A11, a cystine transporter. Many studies have examined the effects of loss-of-function mutations of those proteins on mouse coat color pigmentation. In contrast, much less is known regarding the effects of mutations of the corresponding proteins on human hair pigmentation except for MC1R polymorphisms that lead to pheomelanogenesis. This perspective will discuss what we have/have not learned from mouse coat color pigmentation, with special emphasis on the significant roles of pH and the level of cysteine in melanosomes in controlling melanogenesis. Based on these data, a hypothesis is proposed to explain the diversity of human hair pigmentation.

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

Cited by 13 publications

References 16 publications

The mouse pink‐eyed dilution allele of the P‐gene greatly inhibits eumelanin but not pheomelanin synthesis

The mouse pink‐eyed dilution allele of the P‐gene greatly inhibits eumelanin but not pheomelanin synthesis

The Classical Pink-Eyed Dilution Mutation Affects Angiogenic Responsiveness

Human hair melanins: what we have learned and have not learned from mouse coat color pigmentation

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