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. 2000 May;155(1):213–223. doi: 10.1093/genetics/155.1.213

Defective pigment granule biogenesis and aberrant behavior caused by mutations in the Drosophila AP-3beta adaptin gene ruby.

D Kretzschmar 1, B Poeck 1, H Roth 1, R Ernst 1, A Keller 1, M Porsch 1, R Strauss 1, G O Pflugfelder 1
PMCID: PMC1461058  PMID: 10790396

Abstract

Lysosomal protein trafficking is a fundamental process conserved from yeast to humans. This conservation extends to lysosome-like organelles such as mammalian melanosomes and insect eye pigment granules. Recently, eye and coat color mutations in mouse (mocha and pearl) and Drosophila (garnet and carmine) were shown to affect subunits of the heterotetrameric adaptor protein complex AP-3 involved in vesicle trafficking. Here we demonstrate that the Drosophila eye color mutant ruby is defective in the AP-3beta subunit gene. ruby expression was found in retinal pigment and photoreceptor cells and in the developing central nervous system. ruby mutations lead to a decreased number and altered size of pigment granules in various cell types in and adjacent to the retina. Humans with lesions in the related AP-3betaA gene suffer from Hermansky-Pudlak syndrome, which is caused by defects in a number of lysosome-related organelles. Hermansky-Pudlak patients have a reduced skin pigmentation and suffer from internal bleeding, pulmonary fibrosis, and visual system malfunction. The Drosophila AP-3beta adaptin also appears to be involved in processes other than eye pigment granule biogenesis because all ruby allele combinations tested exhibited defective behavior in a visual fixation paradigm.

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Selected References

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  1. Bainbridge S. P., Bownes M. Staging the metamorphosis of Drosophila melanogaster. J Embryol Exp Morphol. 1981 Dec;66:57–80. [PubMed] [Google Scholar]
  2. Banga S. S., Bloomquist B. T., Brodberg R. K., Pye Q. N., Larrivee D. C., Mason J. M., Boyd J. B., Pak W. L. Cytogenetic characterization of the 4BC region on the X chromosome of Drosophila melanogaster: localization of the mei-9, norpA and omb genes. Chromosoma. 1986;93(4):341–346. doi: 10.1007/BF00327593. [DOI] [PubMed] [Google Scholar]
  3. Bazinet C., Katzen A. L., Morgan M., Mahowald A. P., Lemmon S. K. The Drosophila clathrin heavy chain gene: clathrin function is essential in a multicellular organism. Genetics. 1993 Aug;134(4):1119–1134. doi: 10.1093/genetics/134.4.1119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Beadle G. W., Ephrussi B. The Differentiation of Eye Pigments in Drosophila as Studied by Transplantation. Genetics. 1936 May;21(3):225–247. doi: 10.1093/genetics/21.3.225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bok D. Retinal photoreceptor-pigment epithelium interactions. Friedenwald lecture. Invest Ophthalmol Vis Sci. 1985 Dec;26(12):1659–1694. [PubMed] [Google Scholar]
  6. Brand A. H., Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development. 1993 Jun;118(2):401–415. doi: 10.1242/dev.118.2.401. [DOI] [PubMed] [Google Scholar]
  7. Cavener D. R. Comparison of the consensus sequence flanking translational start sites in Drosophila and vertebrates. Nucleic Acids Res. 1987 Feb 25;15(4):1353–1361. doi: 10.1093/nar/15.4.1353. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cowles C. R., Odorizzi G., Payne G. S., Emr S. D. The AP-3 adaptor complex is essential for cargo-selective transport to the yeast vacuole. Cell. 1997 Oct 3;91(1):109–118. doi: 10.1016/s0092-8674(01)80013-1. [DOI] [PubMed] [Google Scholar]
  9. Dell'Angelica E. C., Klumperman J., Stoorvogel W., Bonifacino J. S. Association of the AP-3 adaptor complex with clathrin. Science. 1998 Apr 17;280(5362):431–434. doi: 10.1126/science.280.5362.431. [DOI] [PubMed] [Google Scholar]
  10. Dell'Angelica E. C., Mullins C., Bonifacino J. S. AP-4, a novel protein complex related to clathrin adaptors. J Biol Chem. 1999 Mar 12;274(11):7278–7285. doi: 10.1074/jbc.274.11.7278. [DOI] [PubMed] [Google Scholar]
  11. Dell'Angelica E. C., Ohno H., Ooi C. E., Rabinovich E., Roche K. W., Bonifacino J. S. AP-3: an adaptor-like protein complex with ubiquitous expression. EMBO J. 1997 Mar 3;16(5):917–928. doi: 10.1093/emboj/16.5.917. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Dell'Angelica E. C., Ooi C. E., Bonifacino J. S. Beta3A-adaptin, a subunit of the adaptor-like complex AP-3. J Biol Chem. 1997 Jun 13;272(24):15078–15084. doi: 10.1074/jbc.272.24.15078. [DOI] [PubMed] [Google Scholar]
  13. Dell'Angelica E. C., Shotelersuk V., Aguilar R. C., Gahl W. A., Bonifacino J. S. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the beta 3A subunit of the AP-3 adaptor. Mol Cell. 1999 Jan;3(1):11–21. doi: 10.1016/s1097-2765(00)80170-7. [DOI] [PubMed] [Google Scholar]
  14. Dreesen T. D., Johnson D. H., Henikoff S. The brown protein of Drosophila melanogaster is similar to the white protein and to components of active transport complexes. Mol Cell Biol. 1988 Dec;8(12):5206–5215. doi: 10.1128/mcb.8.12.5206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Faúndez V., Horng J. T., Kelly R. B. A function for the AP3 coat complex in synaptic vesicle formation from endosomes. Cell. 1998 May 1;93(3):423–432. doi: 10.1016/s0092-8674(00)81170-8. [DOI] [PubMed] [Google Scholar]
  16. Feng L., Seymour A. B., Jiang S., To A., Peden A. A., Novak E. K., Zhen L., Rusiniak M. E., Eicher E. M., Robinson M. S. The beta3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky-Pudlak syndrome and night blindness. Hum Mol Genet. 1999 Feb;8(2):323–330. doi: 10.1093/hmg/8.2.323. [DOI] [PubMed] [Google Scholar]
  17. Gardner J. M., Wildenberg S. C., Keiper N. M., Novak E. K., Rusiniak M. E., Swank R. T., Puri N., Finger J. N., Hagiwara N., Lehman A. L. The mouse pale ear (ep) mutation is the homologue of human Hermansky-Pudlak syndrome. Proc Natl Acad Sci U S A. 1997 Aug 19;94(17):9238–9243. doi: 10.1073/pnas.94.17.9238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Golic K. G., Lindquist S. The FLP recombinase of yeast catalyzes site-specific recombination in the Drosophila genome. Cell. 1989 Nov 3;59(3):499–509. doi: 10.1016/0092-8674(89)90033-0. [DOI] [PubMed] [Google Scholar]
  19. González-Gaitán M., Jäckle H. Role of Drosophila alpha-adaptin in presynaptic vesicle recycling. Cell. 1997 Mar 21;88(6):767–776. doi: 10.1016/s0092-8674(00)81923-6. [DOI] [PubMed] [Google Scholar]
  20. Götz K. G. Visual guidance in Drosophila. Basic Life Sci. 1980;16:391–407. doi: 10.1007/978-1-4684-7968-3_28. [DOI] [PubMed] [Google Scholar]
  21. Hazelwood S., Shotelersuk V., Wildenberg S. C., Chen D., Iwata F., Kaiser-Kupfer M. I., White J. G., King R. A., Gahl W. A. Evidence for locus heterogeneity in Puerto Ricans with Hermansky-Pudlak syndrome. Am J Hum Genet. 1997 Nov;61(5):1088–1094. doi: 10.1086/301611. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Heilker R., Spiess M., Crottet P. Recognition of sorting signals by clathrin adaptors. Bioessays. 1999 Jul;21(7):558–567. doi: 10.1002/(SICI)1521-1878(199907)21:7<558::AID-BIES4>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  23. Hengstenberg R., Götz K. G. Der Einfluss des Schrimpigmentgehalts auf die Helligkeits- und Kontrastwahrnehmung bei Drosophila-Augenmutanten. Kybernetik. 1967 May;3(6):276–285. doi: 10.1007/BF00271510. [DOI] [PubMed] [Google Scholar]
  24. Hindis R., Manor H., Strauss S. Sonographic diagnosis of seminal vesicle cysts in autosomal dominant polycystic kidney disease. J Clin Ultrasound. 1998 May;26(4):221–222. doi: 10.1002/(sici)1097-0096(199805)26:4<221::aid-jcu9>3.0.co;2-f. [DOI] [PubMed] [Google Scholar]
  25. Kantheti P., Qiao X., Diaz M. E., Peden A. A., Meyer G. E., Carskadon S. L., Kapfhamer D., Sufalko D., Robinson M. S., Noebels J. L. Mutation in AP-3 delta in the mocha mouse links endosomal transport to storage deficiency in platelets, melanosomes, and synaptic vesicles. Neuron. 1998 Jul;21(1):111–122. doi: 10.1016/s0896-6273(00)80519-x. [DOI] [PubMed] [Google Scholar]
  26. Le Borgne R., Hoflack B. Mechanisms of protein sorting and coat assembly: insights from the clathrin-coated vesicle pathway. Curr Opin Cell Biol. 1998 Aug;10(4):499–503. doi: 10.1016/s0955-0674(98)80065-3. [DOI] [PubMed] [Google Scholar]
  27. Lloyd V., Ramaswami M., Krämer H. Not just pretty eyes: Drosophila eye-colour mutations and lysosomal delivery. Trends Cell Biol. 1998 Jul;8(7):257–259. doi: 10.1016/s0962-8924(98)01270-7. [DOI] [PubMed] [Google Scholar]
  28. Mangini N. J., Vanable J. W., Jr, Williams M. A., Pinto L. H. The optokinetic nystagmus and ocular pigmentation of hypopigmented mouse mutants. J Comp Neurol. 1985 Nov 8;241(2):191–209. doi: 10.1002/cne.902410207. [DOI] [PubMed] [Google Scholar]
  29. Marcus R. C., Wang L. C., Mason C. A. Retinal axon divergence in the optic chiasm: midline cells are unaffected by the albino mutation. Development. 1996 Mar;122(3):859–868. doi: 10.1242/dev.122.3.859. [DOI] [PubMed] [Google Scholar]
  30. McCarthy A., Nickla H. Morphology of the carnation-light synthetic lethal focus in Drosophila melanogaster. Experientia. 1980 Dec 15;36(12):1361–1362. doi: 10.1007/BF01960098. [DOI] [PubMed] [Google Scholar]
  31. Mostov K., ter Beest M. B., Chapin S. J. Catch the mu1B train to the basolateral surface. Cell. 1999 Oct 15;99(2):121–122. doi: 10.1016/s0092-8674(00)81643-8. [DOI] [PubMed] [Google Scholar]
  32. Mullins C., Hartnell L. M., Wassarman D. A., Bonifacino J. S. Defective expression of the mu3 subunit of the AP-3 adaptor complex in the Drosophila pigmentation mutant carmine. Mol Gen Genet. 1999 Oct;262(3):401–412. doi: 10.1007/s004380051099. [DOI] [PubMed] [Google Scholar]
  33. Newman L. S., McKeever M. O., Okano H. J., Darnell R. B. Beta-NAP, a cerebellar degeneration antigen, is a neuron-specific vesicle coat protein. Cell. 1995 Sep 8;82(5):773–783. doi: 10.1016/0092-8674(95)90474-3. [DOI] [PubMed] [Google Scholar]
  34. Noebels J. L., Sidman R. L. Persistent hypersynchronization of neocortical neurons in the mocha mutant of mouse. J Neurogenet. 1989 Sep;6(1):53–56. doi: 10.3109/01677068909107100. [DOI] [PubMed] [Google Scholar]
  35. O'Connell P. O., Rosbash M. Sequence, structure, and codon preference of the Drosophila ribosomal protein 49 gene. Nucleic Acids Res. 1984 Jul 11;12(13):5495–5513. doi: 10.1093/nar/12.13.5495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Odorizzi G., Cowles C. R., Emr S. D. The AP-3 complex: a coat of many colours. Trends Cell Biol. 1998 Jul;8(7):282–288. doi: 10.1016/s0962-8924(98)01295-1. [DOI] [PubMed] [Google Scholar]
  37. Oh J., Bailin T., Fukai K., Feng G. H., Ho L., Mao J. I., Frenk E., Tamura N., Spritz R. A. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nat Genet. 1996 Nov;14(3):300–306. doi: 10.1038/ng1196-300. [DOI] [PubMed] [Google Scholar]
  38. Ooi C. E., Moreira J. E., Dell'Angelica E. C., Poy G., Wassarman D. A., Bonifacino J. S. Altered expression of a novel adaptin leads to defective pigment granule biogenesis in the Drosophila eye color mutant garnet. EMBO J. 1997 Aug 1;16(15):4508–4518. doi: 10.1093/emboj/16.15.4508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Panek H. R., Stepp J. D., Engle H. M., Marks K. M., Tan P. K., Lemmon S. K., Robinson L. C. Suppressors of YCK-encoded yeast casein kinase 1 deficiency define the four subunits of a novel clathrin AP-like complex. EMBO J. 1997 Jul 16;16(14):4194–4204. doi: 10.1093/emboj/16.14.4194. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pevsner J., Volknandt W., Wong B. R., Scheller R. H. Two rat homologs of clathrin-associated adaptor proteins. Gene. 1994 Sep 2;146(2):279–283. doi: 10.1016/0378-1119(94)90306-9. [DOI] [PubMed] [Google Scholar]
  41. Pflugfelder G. O., Schwarz H., Roth H., Poeck B., Sigl A., Kerscher S., Jonschker B., Pak W. L., Heisenberg M. Genetic and molecular characterization of the optomotor-blind gene locus in Drosophila melanogaster. Genetics. 1990 Sep;126(1):91–104. doi: 10.1093/genetics/126.1.91. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Renfranz P. J., Benzer S. Monoclonal antibody probes discriminate early and late mutant defects in development of the Drosophila retina. Dev Biol. 1989 Dec;136(2):411–429. doi: 10.1016/0012-1606(89)90267-4. [DOI] [PubMed] [Google Scholar]
  43. Robinson M. S. Coats and vesicle budding. Trends Cell Biol. 1997 Mar;7(3):99–102. doi: 10.1016/S0962-8924(96)10048-9. [DOI] [PubMed] [Google Scholar]
  44. Saint Marie R. L., Carlson S. D. The fine structure of neuroglia in the lamina ganglionaris of the housefly, Musca domestica L. J Neurocytol. 1983 Apr;12(2):213–241. doi: 10.1007/BF01148463. [DOI] [PubMed] [Google Scholar]
  45. Schekman R., Orci L. Coat proteins and vesicle budding. Science. 1996 Mar 15;271(5255):1526–1533. doi: 10.1126/science.271.5255.1526. [DOI] [PubMed] [Google Scholar]
  46. Sevrioukov E. A., He J. P., Moghrabi N., Sunio A., Krämer H. A role for the deep orange and carnation eye color genes in lysosomal delivery in Drosophila. Mol Cell. 1999 Oct;4(4):479–486. doi: 10.1016/s1097-2765(00)80199-9. [DOI] [PubMed] [Google Scholar]
  47. Shih W., Gallusser A., Kirchhausen T. A clathrin-binding site in the hinge of the beta 2 chain of mammalian AP-2 complexes. J Biol Chem. 1995 Dec 29;270(52):31083–31090. doi: 10.1074/jbc.270.52.31083. [DOI] [PubMed] [Google Scholar]
  48. Shoup J. R. The development of pigment granules in the eyes of wild type and mutant Drosophila melanogaster. J Cell Biol. 1966 May;29(2):223–249. doi: 10.1083/jcb.29.2.223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Simpson F., Peden A. A., Christopoulou L., Robinson M. S. Characterization of the adaptor-related protein complex, AP-3. J Cell Biol. 1997 May 19;137(4):835–845. doi: 10.1083/jcb.137.4.835. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Spritz R. A. Multi-organellar disorders of pigmentation: intracellular traffic jams in mammals, flies and yeast. Trends Genet. 1999 Sep;15(9):337–340. doi: 10.1016/s0168-9525(99)01785-0. [DOI] [PubMed] [Google Scholar]
  51. Stern C. Somatic Crossing over and Segregation in Drosophila Melanogaster. Genetics. 1936 Nov;21(6):625–730. doi: 10.1093/genetics/21.6.625. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Strauss R., Pichler J. Persistence of orientation toward a temporarily invisible landmark in Drosophila melanogaster. J Comp Physiol A. 1998 Apr;182(4):411–423. doi: 10.1007/s003590050190. [DOI] [PubMed] [Google Scholar]
  53. Swank R. T., Novak E. K., McGarry M. P., Rusiniak M. E., Feng L. Mouse models of Hermansky Pudlak syndrome: a review. Pigment Cell Res. 1998 Apr;11(2):60–80. doi: 10.1111/j.1600-0749.1998.tb00713.x. [DOI] [PubMed] [Google Scholar]
  54. Tearle R. G., Belote J. M., McKeown M., Baker B. S., Howells A. J. Cloning and characterization of the scarlet gene of Drosophila melanogaster. Genetics. 1989 Jul;122(3):595–606. doi: 10.1093/genetics/122.3.595. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Waters M. G., Serafini T., Rothman J. E. 'Coatomer': a cytosolic protein complex containing subunits of non-clathrin-coated Golgi transport vesicles. Nature. 1991 Jan 17;349(6306):248–251. doi: 10.1038/349248a0. [DOI] [PubMed] [Google Scholar]
  56. Williams M. A., Pinto L. H., Gherson J. The retinal pigment epithelium of wild type (C57BL/6J +/+) and pearl mutant (C57BL/6J pe/pe) mice. Invest Ophthalmol Vis Sci. 1985 May;26(5):657–669. [PubMed] [Google Scholar]
  57. Xiong W. C., Montell C. Defective glia induce neuronal apoptosis in the repo visual system of Drosophila. Neuron. 1995 Mar;14(3):581–590. doi: 10.1016/0896-6273(95)90314-3. [DOI] [PubMed] [Google Scholar]
  58. Zhang B., Ganetzky B., Bellen H. J., Murthy V. N. Tailoring uniform coats for synaptic vesicles during endocytosis. Neuron. 1999 Jul;23(3):419–422. doi: 10.1016/s0896-6273(00)80794-1. [DOI] [PubMed] [Google Scholar]
  59. Zhang B., Koh Y. H., Beckstead R. B., Budnik V., Ganetzky B., Bellen H. J. Synaptic vesicle size and number are regulated by a clathrin adaptor protein required for endocytosis. Neuron. 1998 Dec;21(6):1465–1475. doi: 10.1016/s0896-6273(00)80664-9. [DOI] [PubMed] [Google Scholar]
  60. Zinsmaier K. E., Hofbauer A., Heimbeck G., Pflugfelder G. O., Buchner S., Buchner E. A cysteine-string protein is expressed in retina and brain of Drosophila. J Neurogenet. 1990 Nov;7(1):15–29. doi: 10.3109/01677069009084150. [DOI] [PubMed] [Google Scholar]

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