, Volume 16, Issue 3, pp 639–646 | Cite as

The albino mutation of tyrosinase alters ocular angiogenic responsiveness

  • Michael S. RogersEmail author
  • Irit Adini
  • Aaron F. McBride
  • Amy E. Birsner
  • Robert J. D’Amato
Original Paper


We have observed substantial differences in angiogenic responsiveness in mice and have mapped the genetic loci responsible for these differences. We have found that the albino mutation is one of the loci responsible for such differences. Using B6.A consomic strains, we determined that chromosome 7 bears a locus that inhibits VEGF-induced corneal neovascularization. F2 crosses between B6.A<Chromosome 7> consomic mice and C57BL/6J parents along with AXB and BXA recombinant inbred strains demonstrated highest linkage near the tyrosinase gene. This region was named AngVq4. Congenic animals confirmed this locus, but could not demonstrate that the classical tyrosinase albino (c) mutation was causative because of the existence of additional linked loci in the congenic region. However, in 1970, a second tyrosinase albino mutation (c-2J) arose in the C57BL/6J background at Jackson Labs. Testing this strain (C57BL/6J<c-2J>) demonstrated that the albino mutation is sufficient to completely explain the alteration in angiogenic response that we observed in congenic animals. Thus, we conclude that the classical tyrosinase mutation is responsible for AngVq4. In contrast to the cornea, where pigmented animals exhibit increased angiogenic responsiveness, iris neovascularization was inhibited in pigmented animals. These results may partially explain increased aggressiveness in amelanotic melanoma, as well as ethnic differences in diabetic retinopathy and macular degeneration.


QTL mapping Pigment Albino Consomic mouse Cornea Iris DOPA DHI 5,6-Dihydroxyindole 



Authors received support from National Institutes of Health Grants R01 EY12726.


  1. 1.
    Rohan RM, Fernandez A, Udagawa T, Yuan J, D’Amato RJ (2000) Genetic heterogeneity of angiogenesis in mice. Faseb J 14(7):871–876PubMedGoogle Scholar
  2. 2.
    Rogers MS, Rohan RM, Birsner AE, D’Amato RJ (2003) Genetic loci that control vascular endothelial growth factor-induced angiogenesis. Faseb J 17(14):2112–2114Google Scholar
  3. 3.
    Rogers MS, Rohan RM, Birsner AE, D’Amato RJ (2004) Genetic loci that control the angiogenic response to basic fibroblast growth factor. Faseb J 18(10):1050–1059PubMedCrossRefGoogle Scholar
  4. 4.
    Nakai K, Rogers MS, Baba T, Funakoshi T, Birsner AE, Luyindula DS, D’Amato RJ (2009) Genetic loci that control the size of laser-induced choroidal neovascularization. Faseb J 23(7):2235–2243Google Scholar
  5. 5.
    Rogers MS, Birsner AE, D’Amato RJ (2007) The mouse cornea micropocket angiogenesis assay. Nat Protoc 2(10):2545–2550PubMedCrossRefGoogle Scholar
  6. 6.
    Rogers MS, D’Amato RJ (2006) The effect of genetic diversity on angiogenesis. Exp Cell Res 312(5):561–574PubMedCrossRefGoogle Scholar
  7. 7.
    Shaked Y, Bertolini F, Man S, Rogers MS, Cervi D, Foutz T, Rawn K, Voskas D, Dumont DJ, Ben-David Y, Lawler J, Henkin J, Huber J, Hicklin DJ, D’Amato RJ, Kerbel RS (2005) Genetic heterogeneity of the vasculogenic phenotype parallels angiogenesis; Implications for cellular surrogate marker analysis of antiangiogenesis. Cancer Cell 7(1):101–111PubMedGoogle Scholar
  8. 8.
    Land EJ, Ramsden CA, Riley PA (2003) Tyrosinase autoactivation and the chemistry of ortho-quinone amines. Acc Chem Res 36(5):300–308PubMedCrossRefGoogle Scholar
  9. 9.
    Basu S, Nagy JA, Pal S, Vasile E, Eckelhoefer IA, Bliss VS, Manseau EJ, Dasgupta PS, Dvorak HF, Mukhopadhyay D (2001) The neurotransmitter dopamine inhibits angiogenesis induced by vascular permeability factor/vascular endothelial growth factor. Nat Med 7(5):569–574PubMedCrossRefGoogle Scholar
  10. 10.
    Chakroborty D, Sarkar C, Basu B, Dasgupta PS, Basu S (2009) Catecholamines regulate tumor angiogenesis. Cancer Res 69(9):3727–3730PubMedCrossRefGoogle Scholar
  11. 11.
    Ushio-Fukai M, Nakamura Y (2008) Reactive oxygen species and angiogenesis: nADPH oxidase as target for cancer therapy. Cancer Lett 266(1):37–52PubMedCrossRefGoogle Scholar
  12. 12.
    Beermann F, Orlow SJ, Lamoreux ML (2004) The Tyr (albino) locus of the laboratory mouse. Mamm Genome 15(10):749–758PubMedCrossRefGoogle Scholar
  13. 13.
    Haldane JBS, Sprunt AD, Haldane NM (1915) Reduplication in mice. J Genet 5(2):133–135CrossRefGoogle Scholar
  14. 14.
    Page-McCaw PS, Chung SC, Muto A, Roeser T, Staub W, Finger-Baier KC, Korenbrot JI, Baier H (2004) Retinal network adaptation to bright light requires tyrosinase. Nat Neurosci 7(12):1329–1336PubMedCrossRefGoogle Scholar
  15. 15.
    Kenyon BM, Voest EE, Chen CC, Flynn E, Folkman J, D’Amato RJ (1996) A model of angiogenesis in the mouse cornea. Invest Ophthalmol Vis Sci 37(8):1625–1632PubMedGoogle Scholar
  16. 16.
    Wang S, Basten CJ, Zeng Z-B (2007) Windows QTL Cartographer 2.5. 2.5 ednGoogle Scholar
  17. 17.
    Nadeau JH, Singer JB, Matin A, Lander ES (2000) Analysing complex genetic traits with chromosome substitution strains. Nat Genet 24(3):221–225PubMedCrossRefGoogle Scholar
  18. 18.
    Singer JB, Hill AE, Burrage LC, Olszens KR, Song J, Justice M, O’Brien WE, Conti DV, Witte JS, Lander ES, Nadeau JH (2004) Genetic dissection of complex traits with chromosome substitution strains of mice. Science 304(5669):445–448PubMedCrossRefGoogle Scholar
  19. 19.
    Rogers MS, Boyartchuk V, Rohan RM, Birsner AE, Dietrich WF, D’Amato RJ (2012) The classical pink-eyed dilution mutation affects angiogenic responsiveness. PLoS ONE 7(5):e35237PubMedCrossRefGoogle Scholar
  20. 20.
    Alexeev V, Yoon K (1998) Stable and inheritable changes in genotype and phenotype of albino melanocytes induced by an RNA-DNA oligonucleotide. Nat Biotechnol 16(13):1343–1346PubMedCrossRefGoogle Scholar
  21. 21.
    Pham CL, Leong SL, Ali FE, Kenche VB, Hill AF, Gras SL, Barnham KJ, Cappai R (2009) Dopamine and the dopamine oxidation product 5,6-dihydroxylindole promote distinct on-pathway and off-pathway aggregation of alpha-synuclein in a pH-dependent manner. J Mol Biol 387(3):771–785PubMedCrossRefGoogle Scholar
  22. 22.
    Chesney J, Metz C, Bacher M, Peng T, Meinhardt A, Bucala R (1999) An essential role for macrophage migration inhibitory factor (MIF) in angiogenesis and the growth of a murine lymphoma. Mol Med 5(3):181–191PubMedGoogle Scholar
  23. 23.
    Rosengren E, Bucala R, Aman P, Jacobsson L, Odh G, Metz CN, Rorsman H (1996) The immunoregulatory mediator macrophage migration inhibitory factor (MIF) catalyzes a tautomerization reaction. Mol Med 2(1):143–149PubMedGoogle Scholar
  24. 24.
    Khoufache K, Bazin S, Girard K, Guillemette J, Roy MC, Verreault JP, Al-Abed Y, Foster W, Akoum A (2012) Macrophage migration inhibitory factor antagonist blocks the development of endometriosis in vivo. PLoS ONE 7(5):e37264PubMedCrossRefGoogle Scholar
  25. 25.
    Yasuda M, Ohzeki Y, Shimizu S, Naito S, Ohtsuru A, Yamamoto T, Kuroiwa Y (1999) Stimulation of in vitro angiogenesis by hydrogen peroxide and the relation with ETS-1 in endothelial cells. Life Sci 64(4):249–258PubMedCrossRefGoogle Scholar
  26. 26.
    Chalothorn D, Zhang H, Clayton JA, Thomas SA, Faber JE (2005) Catecholamines augment collateral vessel growth and angiogenesis in hindlimb ischemia. Am J Physiol Heart Circ Physiol 289(2):H947–H959PubMedCrossRefGoogle Scholar
  27. 27.
    Chua CC, Hamdy RC, Chua BH (1998) Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells. Free Radic Biol Med 25(8):891–897PubMedCrossRefGoogle Scholar
  28. 28.
    Ushio-Fukai M, Alexander RW (2004) Reactive oxygen species as mediators of angiogenesis signaling: role of NAD(P)H oxidase. Mol Cell Biochem 264(1–2):85–97PubMedCrossRefGoogle Scholar
  29. 29.
    Sato H, Sato M, Kanai H, Uchiyama T, Iso T, Ohyama Y, Sakamoto H, Tamura J, Nagai R, Kurabayashi M (2005) Mitochondrial reactive oxygen species and c-Src play a critical role in hypoxic response in vascular smooth muscle cells. Cardiovasc Res 67(4):714–722PubMedCrossRefGoogle Scholar
  30. 30.
    Ushio-Fukai M, Tang Y, Fukai T, Dikalov SI, Ma Y, Fujimoto M, Quinn MT, Pagano PJ, Johnson C, Alexander RW (2002) Novel role of gp91(phox)-containing NAD(P)H oxidase in vascular endothelial growth factor-induced signaling and angiogenesis. Circ Res 91(12):1160–1167PubMedCrossRefGoogle Scholar
  31. 31.
    Ikeda S, Yamaoka-Tojo M, Hilenski L, Patrushev NA, Anwar GM, Quinn MT, Ushio-Fukai M (2005) IQGAP1 regulates reactive oxygen species-dependent endothelial cell migration through interacting with Nox2. Arterioscler Thromb Vasc Biol 25(11):2295–2300PubMedCrossRefGoogle Scholar
  32. 32.
    Notani K, Shindoh M, Yamazaki Y, Nakamura H, Watanabe M, Kogoh T, Ferguson MM, Fukuda H (2002) Amelanotic malignant melanomas of the oral mucosa. Br J Oral Maxillofac Surg 40(3):195–200PubMedCrossRefGoogle Scholar
  33. 33.
    Ohashi K, Kasuga T, Tanaka N, Enomoto S, Horiuchi J, Okada N (1992) Malignant melanomas of the oral cavity: heterogeneity of pathological and clinical features. Virchows Arch A Pathol Anat Histopathol 420(1):43–50PubMedCrossRefGoogle Scholar
  34. 34.
    Marcoval J, Moreno A, Graells J, Vidal A, Escriba JM, Garcia-Ramirez M, Fabra A (1997) Angiogenesis and malignant melanoma. Angiogenesis is related to the development of vertical (tumorigenic) growth phase. J Cutan Pathol 24(4):212–218PubMedCrossRefGoogle Scholar
  35. 35.
    Weiter JJ, Delori FC, Wing GL, Fitch KA (1986) Retinal pigment epithelial lipofuscin and melanin and choroidal melanin in human eyes. Invest Ophthalmol Vis Sci 27(2):145–152PubMedGoogle Scholar
  36. 36.
    Gregor Z, Joffe L (1978) Senile macular changes in the black African. Br J Ophthalmol 62(8):547–550PubMedCrossRefGoogle Scholar
  37. 37.
    Sommer A, Tielsch JM, Katz J, Quigley HA, Gottsch JD, Javitt JC, Martone JF, Royall RM, Witt KA, Ezrine S (1991) Racial differences in the cause-specific prevalence of blindness in east Baltimore. N Engl J Med 325(20):1412–1417PubMedCrossRefGoogle Scholar
  38. 38.
    Emanuele N, Sacks J, Klein R, Reda D, Anderson R, Duckworth W, Abraira C (2005) Ethnicity, race, and baseline retinopathy correlates in the veterans affairs diabetes trial. Diabetes Care 28(8):1954–1958PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media Dordrecht 2013

Authors and Affiliations

  • Michael S. Rogers
    • 1
    Email author
  • Irit Adini
    • 1
  • Aaron F. McBride
    • 1
  • Amy E. Birsner
    • 1
  • Robert J. D’Amato
    • 1
    • 2
  1. 1.Vascular Biology ProgramChildren’s Hospital Boston, Harvard Medical SchoolBostonUSA
  2. 2.Department of OphthalmologyHarvard Medical SchoolBostonUSA

Personalised recommendations