Inactivation of Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation
PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel−/−). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel−/− melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.
Vyšlo v časopise:
Inactivation of Alters Melanosome Shape But Has Only a Subtle Effect on Visible Pigmentation. PLoS Genet 7(9): e32767. doi:10.1371/journal.pgen.1002285
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002285
Souhrn
PMEL is an amyloidogenic protein that appears to be exclusively expressed in pigment cells and forms intralumenal fibrils within early stage melanosomes upon which eumelanins deposit in later stages. PMEL is well conserved among vertebrates, and allelic variants in several species are associated with reduced levels of eumelanin in epidermal tissues. However, in most of these cases it is not clear whether the allelic variants reflect gain-of-function or loss-of-function, and no complete PMEL loss-of-function has been reported in a mammal. Here, we have created a mouse line in which the Pmel gene has been inactivated (Pmel−/−). These mice are fully viable, fertile, and display no obvious developmental defects. Melanosomes within Pmel−/− melanocytes are spherical in contrast to the oblong shape present in wild-type animals. This feature was documented in primary cultures of skin-derived melanocytes as well as in retinal pigment epithelium cells and in uveal melanocytes. Inactivation of Pmel has only a mild effect on the coat color phenotype in four different genetic backgrounds, with the clearest effect in mice also carrying the brown/Tyrp1 mutation. This phenotype, which is similar to that observed with the spontaneous silver mutation in mice, strongly suggests that other previously described alleles in vertebrates with more striking effects on pigmentation are dominant-negative mutations. Despite a mild effect on visible pigmentation, inactivation of Pmel led to a substantial reduction in eumelanin content in hair, which demonstrates that PMEL has a critical role for maintaining efficient epidermal pigmentation.
Zdroje
1. ItoSWakamatsuK 2008 Chemistry of mixed melanogenesis--pivotal roles of dopaquinone. Photochem Photobiol 84 582 592
2. FurumuraMSakaiCPotterfSBVieiraWDBarshGS 1998 Characterization of genes modulated during pheomelanogenesis using differential display. Proc Natl Acad Sci U S A 95 7374 7378
3. BaxterLLPavanWJ 2003 Pmel17 expression is Mitf-dependent and reveals cranial melanoblast migration during murine development. Gene Expr Patterns 3 703 707
4. TheosACTruschelSTRaposoGMarksMS 2005 The Silver locus product Pmel17/gp100/Silv/ME20: controversial in name and in function. Pigment Cell Res 18 322 336
5. ChakrabortyAKPlattJTKimKKKwonBSBennettDC 1996 Polymerization of 5,6-dihydroxyindole-2-carboxylic acid to melanin by the pmel 17/silver locus protein. Eur J Biochem 236 180 188
6. FowlerDMKoulovAVAlory-JostCMarksMSBalchWE 2006 Functional amyloid formation within mammalian tissue. PLoS Biol 4 e6 doi:10.1371/journal.pbio.0040006
7. LeeZHHouLMoellmannGKuklinskaEAntolK 1996 Characterization and subcellular localization of human Pmel 17/silver, a 110-kDa (pre)melanosomal membrane protein associated with 5,6,-dihydroxyindole-2-carboxylic acid (DHICA) converting activity. J Invest Dermatol 106 605 610
8. WattBRaposoGMarksSM 2010 Pmel17: An amyloid determinant of organelle structure. RigacciSBucciantiniM Functional Amyloid Aggregation Kerala Research Signpost
9. Martinez-EsparzaMJimenez-CervantesCSolanoFLozanoJAGarcia-BorronJC 2000 Regulation of the murine silver locus product (gp87) by the hypopigmenting cytokines TGF-beta1 and TNF-alpha. Pigment Cell Res 13 120 126
10. SolanoFMartinez-EsparzaMJimenez-CervantesCHillSPLozanoJA 2000 New insights on the structure of the mouse silver locus and on the function of the silver protein. Pigment Cell Res 13 Suppl 8 118 124
11. TheosACBersonJFTheosSCHermanKEHarperDC 2006 Dual loss of ER export and endocytic signals with altered melanosome morphology in the silver mutation of Pmel17. Mol Biol Cell 17 3598 3612
12. DunnLCThigpenLW 1930 The silver mouse: a recessive color variation. Journal of Heredity 21 495 498
13. LamoreuxMLDelmasVLarueLBennetCD 2010 The Colors of Mice: A Model Genetic Network: Wiley-Blackwell
14. SilversWK 1979 The Coat Colors of Mice. A Model for Mammalian Gene Action and Interaction New York, NY Springer-Verlag 379
15. KarlssonACKerjeSHallbookFJensenP 2009 The Dominant white mutation in the PMEL17 gene does not cause visual impairment in chickens. Vet Ophthalmol 12 292 298
16. KerjeSSharmaPGunnarssonUKimHBagchiS 2004 The Dominant white, Dun and Smoky color variants in chicken are associated with insertion/deletion polymorphisms in the PMEL17 gene. Genetics 168 1507 1518
17. BrumbaughJA 1971 The ultrastructural effects of the I and S loci upon black-red melanin differentiation in the fowl. Develop Biol 24 394 412
18. JimbowKSzaboGFitzpatrickTB 1974 Ultrastructural investigation of autophagocytosis of melanosomes and programmed death of melanocytes in White Leghorn feathers: a study of morphogenetic events leading to hypomelanosis. Dev Biol 36 8 23
19. BrumbaughJALeeKW 1975 The gene action and function of two dopa oxidase positive melanocyte mutants of the fowl. Genetics 81 333 347
20. TheosACTruschelSTTenzaDHurbainIHarperDC 2006 A lumenal domain-dependent pathway for sorting to intralumenal vesicles of multivesicular endosomes involved in organelle morphogenesis. Dev Cell 10 343 354
21. WattBvan NielGFowlerDMHurbainILukKC 2009 N-terminal domains elicit formation of functional Pmel17 amyloid fibrils. J Biol Chem 284 35543 35555
22. BrunbergEAnderssonLCothranGSandbergKMikkoS 2006 A missense mutation in PMEL17 is associated with the Silver coat color in the horse. BMC Genet 7 46
23. SchonthalerHBLampertJMvon LintigJSchwarzHGeislerR 2005 A mutation in the silver gene leads to defects in melanosome biogenesis and alterations in the visual system in the zebrafish mutant fading vision. Dev Biol 284 421 436
24. ClarkLAWahlJMReesCAMurphyKE 2006 Retrotransposon insertion in SILV is responsible for merle patterning of the domestic dog. Proc Natl Acad Sci U S A
25. KuhnCWeikardR 2007 An investigation into the genetic background of coat colour dilution in a Charolais x German Holstein F2 resource population. Anim Genet 38 109 113
26. MontoliuLOettingWSBennettDC 2010 European Society for Pigment Cell Research. World Wide Web (URL: http://www.espcr.org/micemut)
27. BultCJEppigJTKadinJARichardsonJEBlakeJA 2008 The Mouse Genome Database (MGD): mouse biology and model systems. Nucleic Acids Res 36 D724 728
28. WattBTenzaDLemmonMAKerjeSRaposoGAnderssonLMarksSM 2011 Mutations that alter the PMEL transmembrane domain confer toxicity to functional PMEL amyloid. PLoS Genet 7 e1002286 doi:10.1371/journal.pgen.1002286
29. LallemandYLuriaVHaffner-KrauszRLonaiP 1998 Maternally expressed PGK-Cre transgene as a tool for early and uniform activation of the Cre site-specific recombinase. Transgenic Res 7 105 112
30. HurbainIGeertsWJBoudierTMarcoSVerkleijAJ 2008 Electron tomography of early melanosomes: implications for melanogenesis and the generation of fibrillar amyloid sheets. Proc Natl Acad Sci U S A 105 19726 19731
31. RaposoGTenzaDMurphyDMBersonJFMarksMS 2001 Distinct protein sorting and localization to premelanosomes, melanosomes, and lysosomes in pigmented melanocytic cells. J Cell Biol 152 809 824
32. HarperDCTheosACHermanKETenzaDRaposoG 2008 Premelanosome amyloid-like fibrils are composed of only golgi-processed forms of Pmel17 that have been proteolytically processed in endosomes. J Biol Chem 283 2307 2322
33. ItoSNakanishiYValenzuelaRKBrilliantMHKolbeL 2011 Usefulness of alkaline hydrogen peroxide oxidation to analyze eumelanin and pheomelanin in various tissue samples: application to chemical analysis of human hair melanins. Pigment Cell Melanoma Res In press
34. OzekiHItoSWakamatsuKThodyAJ 1996 Spectrophotometric characterization of eumelanin and pheomelanin in hair. Pigment Cell Res 9 265 270
35. WakamatsuKItoS 2002 Advanced chemical methods in melanin determination. Pigment Cell Res 15 174 183
36. WakamatsuKItoSReesJL 2002 The usefulness of 4-amino-3-hydroxyphenylalanine as a specific marker of pheomelanin. Pigment Cell Res 15 225 232
37. DurbinRMAbecasisGRAltshulerDLAutonABrooksLD 2010 A map of human genome variation from population-scale sequencing. Nature 467 1061 1073
38. FutterCE 2006 The molecular regulation of organelle transport in mammalian retinal pigment epithelial cells. Pigment Cell Res 19 104 111
39. LamoreuxMLWakamatsuKItoS 2001 Interaction of major coat color gene functions in mice as studied by chemical analysis of eumelanin and pheomelanin. Pigment Cell Res 14 23 31
40. KobayashiTImokawaGBennettDCHearingVJ 1998 Tyrosinase stabilization by Tyrp1 (the brown locus protein). J Biol Chem 273 31801 31805
41. MangaPBoissyREPifko-HirstSZhouBKOrlowSJ 2001 Mislocalization of melanosomal proteins in melanocytes from mice with oculocutaneous albinism type 2. Exp Eye Res 72 695 710
42. SponenbergDPRothschildMF 2001 Genetics of coat colour and hair texture. RuvinskyASampsonJ The Genetics of the Dog New York, NY CABI Publishing 61 685
43. LevinMDLuMMPetrenkoNBHawkinsBJGuptaTH 2009 Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. J Clin Invest 119 3420 3436
44. SulemPGudbjartssonDFStaceySNHelgasonARafnarT 2007 Genetic determinants of hair, eye and skin pigmentation in Europeans. Nat Genet 39 1443 1452
45. BishopDTDemenaisFIlesMMHarlandMTaylorJC 2009 Genome-wide association study identifies three loci associated with melanoma risk. Nat Genet 41 920 925
46. AnderssonLSJurasRRamseyDTEason-ButlerJEwartS 2008 Equine Multiple Congenital Ocular Anomalies maps to a 4.9 megabase interval on horse chromosome 6. BMC Genet 9 88
47. RamseyDTEwartSLRenderJACookCSLatimerCA 1999 Congenital ocular abnormalities of Rocky Mountain Horses. Vet Ophthalmol 2 47 59
48. NagyARossantJNagyRAbramow-NewerlyWRoderJC 1993 Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc Natl Acad Sci U S A 90 8424 8428
49. JimenezMTsukamotoKHearingVJ 1991 Tyrosinases from two different loci are expressed by normal and by transformed melanocytes. J Biol Chem 266 1147 1156
50. BersonJFHarperDCTenzaDRaposoGMarksMS 2001 Pmel17 initiates premelanosome morphogenesis within multivesicular bodies. Mol Biol Cell 12 3451 3464
51. SviderskayaEVBennettDCHoLBailinTLeeST 1997 Complementation of hypopigmentation in p-mutant (pink-eyed dilution) mouse melanocytes by normal human P cDNA, and defective complementation by OCA2 mutant sequences. J Invest Dermatol 108 30 34
52. SettySRTenzaDTruschelSTChouESviderskayaEV 2007 BLOC-1 is required for cargo-specific sorting from vacuolar early endosomes toward lysosome-related organelles. Mol Biol Cell 18 768 780
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2011 Číslo 9
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD
- The Evolutionarily Conserved Longevity Determinants HCF-1 and SIR-2.1/SIRT1 Collaborate to Regulate DAF-16/FOXO
- Genome-Wide Analysis of Heteroduplex DNA in Mismatch Repair–Deficient Yeast Cells Reveals Novel Properties of Meiotic Recombination Pathways
- Genetic Variants at Chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 Influence the Risk of Breast Cancer in Men