Drosophila as a Model for Human Disease

  • Ruth Johnson
  • Ross Cagan

Abstract

Drosophila melanogaster has proved a remarkable genetically tractable model organism that continues to provide significant contributions to our understanding of numerous biological processes. In this chapter we discuss insights into a variety of human diseases that have been gained directly from studies conducted in fly labs. These include discoveries relating to the basic biology of diseases (the signaling pathways, for example, that may contribute to disease states), new loci implicated in disease progression or susceptibility (uncovered in large-scale screens and verified in situ using often ingenious assays) and the identification of pharmacological reagents to treat diseases (also identified and tested in well-designed screens and assays). Because genomes, biological processes, and responses have been well conserved, and particularly with the current trend in translational research, studies in flies continue to build a strong foundation for disease studies. Those discussed in this chapter include cancer, neurodegenerative diseases, heart disease, diabetes and metabolic diseases, addiction, and sleep disorders.

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References

  1. 1.
    Andretic R, van Swinderen B, Greenspan RJ (2005) Dopaminergic modulation of arousal in Drosophila. Curr Biol 15(13):1165–1175CrossRefPubMedGoogle Scholar
  2. 2.
    Adams MD, Celniker SE, Holt RA et al (2000) The genome sequence of Drosophila melanogaster. Science 287(5461):2185–2195CrossRefPubMedGoogle Scholar
  3. 3.
    Berger KH, Heberlein U, Moore MS (2004) Rapid and chronic: two distinct forms of ethanol tolerance in Drosophila. Alcohol Clin Exp Res 28(10):1469–1480CrossRefPubMedGoogle Scholar
  4. 4.
    Bier E (2005) Drosophila, the golden bug, emerges as a tool for human genetics. Nat Rev Genet 6(1):9–23CrossRefPubMedGoogle Scholar
  5. 5.
    Bier E, Bodmer R (2004) Drosophila, an emerging model for cardiac disease. Gene 342(1):1–11CrossRefPubMedGoogle Scholar
  6. 6.
    Bilder D (2004) Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev 18(16):1909–1925CrossRefPubMedGoogle Scholar
  7. 7.
    Bilder D, Li M, Perrimon N (2000) Cooperative regulation of cell polarity and growth by Drosophila tumor suppressors. Science 289(5476):113–116CrossRefPubMedGoogle Scholar
  8. 8.
    Bilen J, Bonini NM (2005) Drosophila as a model for human neurodegenerative disease. Annu Rev Genet 39:153–171CrossRefPubMedGoogle Scholar
  9. 9.
    Bjorklund M, Taipale M, Varjosalo M et al (2006) Identification of pathways regulating cell size and cell-cycle progression by RNAi. Nature 439(7079):1009–1013CrossRefPubMedGoogle Scholar
  10. 10.
    Brennecke J, Hipfner DR, Stark A, Russell RB, Cohen SM (2003) bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell 113(1):25–36CrossRefPubMedGoogle Scholar
  11. 11.
    Brumby AM, Richardson HE (2003) scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. Embo J 22(21):5769–5779CrossRefPubMedGoogle Scholar
  12. 12.
    Brumby AM, Richardson HE (2005) Using Drosophila melanogaster to map human cancer pathways. Nat Rev Cancer 5(8):626–639CrossRefPubMedGoogle Scholar
  13. 13.
    Bryant PJ, Schubiger G (1971) Giant and duplicated imagi-nal discs in a new lethal mutant of Drosophila melanogaster. Dev Biol 24(2):233–263CrossRefPubMedGoogle Scholar
  14. 14.
    Bryant PJ, Levinson P (1985) Intrinsic growth control in the imaginal primordia of Drosophila, and the autonomous action of a lethal mutation causing overgrowth. Dev Biol 107(2):355–363CrossRefPubMedGoogle Scholar
  15. 15.
    Busygina V, Kottemann MC, Scott KL, Plon SE, Bale AE (2004) Hypermutability in a Drosophila model for multiple endocrine neoplasia type 1. Hum Mol Genet 13(20):2399–2408CrossRefPubMedGoogle Scholar
  16. 16.
    Cirelli C, Bushey D (2008) Sleep and wakefulness in Drosophila melanogaster. Ann NY Acad Sci 1129:323–329CrossRefPubMedGoogle Scholar
  17. 17.
    Colombani J, Raisin S, Pantalacci S et al (2003) A nutrient sensor mechanism controls Drosophila growth. Cell 114(6):739–749CrossRefPubMedGoogle Scholar
  18. 18.
    de la Cova C, Abril M, Bellosta P, Gallant P, Johnston LA (2004) Drosophila myc regulates organ size by inducing cell competition. Cell 117(1):107–116CrossRefPubMedGoogle Scholar
  19. 19.
    Dimova DK, Stevaux O, Frolov MV, Dyson NJ (2003) Cell cycle-dependent and cell cycle-independent control of transcription by the Drosophila E2F/RB pathway. Genes Dev 17(18):2308–2320CrossRefPubMedGoogle Scholar
  20. 20.
    Doroquez DB, Rebay I (2006) Signal integration during development: mechanisms of EGFR and Notch pathway function and cross-talk. Crit Rev Biochem Mol Biol 41(6):339–385CrossRefPubMedGoogle Scholar
  21. 21.
    Duman-Scheel M, Johnston LA, Du W (2004) Repression of dMyc expression by Wingless promotes Rbf-induced G1 arrest in the presumptive Drosophila wing margin. Proc Natl Acad Sci USA 101(11):3857–3862CrossRefPubMedGoogle Scholar
  22. 22.
    Edgar BA, Britton J, de la Cruz AF et al (2001) Pattern- and growth-linked cell cycles in Drosophila developmen. Novartis Found Symp 237:3–12 discussion 12-8CrossRefPubMedGoogle Scholar
  23. 23.
    Ellisen LW, Bird J, West DC et al (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66(4):649–661CrossRefPubMedGoogle Scholar
  24. 24.
    Feany MB, Bender WW (2000) A Drosophila model of Parkinson's disease. Nature 404(6776):394–398CrossRefPubMedGoogle Scholar
  25. 25.
    Ferres-Marco D, Gutierrez-Garcia I, Vallejo DM et al (2006) Epigenetic silencers and Notch collaborate to promote malignant tumours by Rb silencing. Nature 439(7075):430–436CrossRefPubMedGoogle Scholar
  26. 26.
    Finelli A, Kelkar A, Song HJ, Yang H, Konsolaki M (2004) A model for studying Alzheimer's Abeta42-induced toxicity in Drosophila melanogaster. Mol Cell Neurosci 26(3):365–375CrossRefPubMedGoogle Scholar
  27. 27.
    Firth LC, Baker NE (2005) Extracellular signals responsible for spatially regulated proliferation in the differentiating Drosophila eye. Dev Cell 8(4):541–551CrossRefPubMedGoogle Scholar
  28. 28.
    Franz DN, Leonard J, Tudor C et al (2006) Rapamycin causes regression of astrocytomas in tuberous sclerosis complex. Ann Neurol 59(3):490–498CrossRefPubMedGoogle Scholar
  29. 29.
    Frolov M V, Huen DS, Stevaux O et al (2001) Functional antagonism between E2F family members. Genes Dev 15(16):2146–2160CrossRefPubMedGoogle Scholar
  30. 30.
    Gao X, Zhang Y, Arrazola P et al (2002) Tsc tumour suppressor proteins antagonize amino-acid-TOR signalling. Nat Cell Biol 4(9):699–704CrossRefPubMedGoogle Scholar
  31. 31.
    Genovese C, Trani D, Caputi M, Claudio PP (2006) Cell cycle control and beyond: emerging roles for the retinoblas-toma gene family. Oncogene 25(38):5201–5209CrossRefPubMedGoogle Scholar
  32. 32.
    Hall A (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33(Pt 5):891–895PubMedGoogle Scholar
  33. 33.
    Hariharan IK, Bilder D (2006) Regulation of imaginal disc growth by tumor-suppressor genes in Drosophila. Annu Rev Genet 40:335–361CrossRefPubMedGoogle Scholar
  34. 34.
    Harvey K, Tapon N (2007) The Salvador-Warts-Hippo pathway – an emerging tumour-suppressor network. Nat Rev Cancer 7(3):182–191CrossRefPubMedGoogle Scholar
  35. 35.
    Hay BA, Guo M (2006) Caspase-dependent cell death in Drosophila. Annu Rev Cell Dev Biol 22:623–650CrossRefPubMedGoogle Scholar
  36. 36.
    Hendricks JC (2003) Invited review: sleeping flies don't lie: the use of Drosophila melanogaster to study sleep and circa-dian rhythms. J Appl Physiol 94:1660–1672 discussion 1673PubMedGoogle Scholar
  37. 37.
    Hipfner DR, Cohen SM (2003) The Drosophila sterile-20 kinase slik controls cell proliferation and apoptosis during imaginal disc development. PLoS Biol 1(2):E35CrossRefPubMedGoogle Scholar
  38. 38.
    Hisaoka M, Tanaka A, Hashimoto H (2002) Molecular alterations of h-warts/LATS1 tumor suppressor in human soft tissue sarcoma. Lab Invest 82(10):1427–1435PubMedGoogle Scholar
  39. 39.
    Huntington's Disease Collaborative Research Group (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. Cell 72(6):971–983CrossRefGoogle Scholar
  40. 40.
    Igaki T, Pagliarini RA, Xu T (2006) Loss of cell polarity drives tumor growth and invasion through JNK activation in Drosophila. Curr Biol 16(11):1139–1146CrossRefPubMedGoogle Scholar
  41. 41.
    Ishizawar R, Parsons SJ (2004) c-Src and cooperating partners in human cancer. Cancer Cell 6(3):209–214CrossRefPubMedGoogle Scholar
  42. 42.
    Ito N, Rubin GM (1999) gigas, a Drosophila homolog of tuberous sclerosis gene product-2, regulates the cell cycle. Cell 96(4):529–539CrossRefPubMedGoogle Scholar
  43. 43.
    Johnston LA, Prober DA, Edgar BA, Eisenman RN, Gallant P (1999) Drosophila myc regulates cellular growth during development. Cell 98(6):779–790CrossRefPubMedGoogle Scholar
  44. 44.
    Kango-Singh M, Halder G (2004) Drosophila as an emerging model to study metastasis. Genome Biol 5(4):216CrossRefPubMedGoogle Scholar
  45. 45.
    Karmann H, Mialhe P (1976) Glucose, insulin and glucagon in the diabetic goose. Horm Metab Res 8(6):419–426CrossRefPubMedGoogle Scholar
  46. 46.
    Kim SK, Rulifson EJ (2004) Conserved mechanisms of glucose sensing and regulation by Drosophila corpora cardiaca cells. Nature 431(7006):316–320CrossRefPubMedGoogle Scholar
  47. 47.
    Knust E (2002) Regulation of epithelial cell shape and polarity by cell-cell adhesion (Review). Mol Membr Biol 19(2):113–120CrossRefPubMedGoogle Scholar
  48. 48.
    Koh K, Evans JM, Hendricks JC, Sehgal A (2006) A Drosophila model for age-associated changes in sleep:wake cycles. Proc Natl Acad Sci USA 103(37):13843–13847CrossRefPubMedGoogle Scholar
  49. 49.
    Lee MJ, Stephenson DA (2007) Recent developments in neurofibromatosis type 1. Curr Opin Neurol 20(2):135–141CrossRefPubMedGoogle Scholar
  50. 50.
    Lee T, Luo L (2001) Mosaic analysis with a repressible cell marker (MARCM) for Drosophila neural development. Trends Neurosci 24(5):251–254CrossRefPubMedGoogle Scholar
  51. 51.
    Levy-Lahad E, Wasco W, Poorkaj P et al (1995) Candidate gene for the chromosome 1 familial Alzheimer's disease locus. Science 269(5226):973–977CrossRefPubMedGoogle Scholar
  52. 52.
    Lugaresi E, Medori R, Montagna P et al (1986) Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 315(16):997–1003PubMedCrossRefGoogle Scholar
  53. 53.
    Luong N, Davies CR, Wessells RJ et al (2006) Activated FOXO-mediated insulin resistance is blocked by reduction of TOR activity. Cell Metab 4(2):133–142CrossRefPubMedGoogle Scholar
  54. 54.
    McGuire SE, Roman G, Davis RL (2004) Gene expression systems in Drosophila: a synthesis of time and space. Trends Genet 20(8):384–391CrossRefPubMedGoogle Scholar
  55. 55.
    Moberg KH, Bell DW, Wahrer DC, Haber DA, Hariharan IK (2001) Archipelago regulates Cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413(6853):311–316CrossRefPubMedGoogle Scholar
  56. 56.
    Moon NS, Di Stefano L, Dyson N (2006) A gradient of epidermal growth factor receptor signaling determines the sensitivity of rbf1 mutant cells to E2F-dependent apoptosis. Mol Cell Biol 26(20):7601–7615CrossRefPubMedGoogle Scholar
  57. 57.
    Moreno E, Basler K (2004) dMyc transforms cells into super-competitors. Cell 117(1):117–129CrossRefPubMedGoogle Scholar
  58. 58.
    Mumm JS, Kopan R (2000) Notch signaling: from the outside in. Dev Biol 228(2):151–165CrossRefPubMedGoogle Scholar
  59. 59.
    Ocorr K, Akasaka T, Bodmer R (2007) Age-related cardiac disease model of Drosophila. Mech Ageing Dev 128(1):112–116CrossRefPubMedGoogle Scholar
  60. 60.
    Pagliarini RA, Xu T (2003) A genetic screen in Drosophila for metastatic behavior. Science 302(5648):1227–1231CrossRefPubMedGoogle Scholar
  61. 61.
    Pan D, Dong J, Zhang Y, Gao X (2004) Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol 14(2):78–85CrossRefPubMedGoogle Scholar
  62. 62.
    Papaconstantinou M, Wu Y, Pretorius HN et al (2005) Menin is a regulator of the stress response in Drosophila melano-gaster. Mol Cell Biol 25(22):9960–9972CrossRefPubMedGoogle Scholar
  63. 63.
    Read RD, Goodfellow PJ, Mardis ER et al (2005) A Drosophila model of multiple endocrine neoplasia type 2. Genetics 171(3):1057–1081CrossRefPubMedGoogle Scholar
  64. 64.
    Rodan AR, Kiger JA Jr, Heberlein U (2002) Functional dissection of neuroanatomical loci regulating ethanol sensitivity in Drosophila. J Neurosci 22(21):9490–9501PubMedGoogle Scholar
  65. 65.
    Rothenfluh A, Heberlein U (2002) Drugs, flies, and videotape: the effects of ethanol and cocaine on Drosophila locomotion. Curr Opin Neurobiol 12(6):639–645CrossRefPubMedGoogle Scholar
  66. 66.
    Rothenfluh A, Threlkeld RJ, Bainton RJ et al (2006) Distinct behavioral responses to ethanol are regulated by alternate RhoGAP18B isoforms. Cell 127(1):199–211CrossRefPubMedGoogle Scholar
  67. 67.
    Rulifson EJ, Kim SK, Nusse R (2002) Ablation of insulin-producing neurons in flies: growth and diabetic phenotypes. Science 296(5570):1118–1120CrossRefPubMedGoogle Scholar
  68. 68.
    Ryder E, Russell S (2003) Transposable elements as tools for genomics and genetics in Drosophila. Brief Funct Genomic Proteomic 2(1):57–71CrossRefPubMedGoogle Scholar
  69. 69.
    Sang TK, Jackson GR (2005) Drosophila models of neuro-degenerative disease. NeuroRx 2(3):438–446CrossRefPubMedGoogle Scholar
  70. 70.
    Schimmer AD, Dalili S, Batey RA, Riedl SJ (2006) Targeting XIAP for the treatment of malignancy. Cell Death Differ 13(2):179–188CrossRefPubMedGoogle Scholar
  71. 71.
    Schmeichel KL (2004) A fly's eye view of tumor progression and metastasis. Breast Cancer Res 6(2):82–83CrossRefPubMedGoogle Scholar
  72. 72.
    Scholz H, Ramond J, Singh CM, Heberlein U (2000) Functional ethanol tolerance in Drosophila. Neuron 28(1):261–271CrossRefPubMedGoogle Scholar
  73. 73.
    Scholz H, Franz M, Heberlein U (2005) The hangover gene defines a stress pathway required for ethanol tolerance development. Nature 436(7052):845–847CrossRefPubMedGoogle Scholar
  74. 74.
    Seugnet L, Boero J, Gottschalk L, Duntley SP, Shaw PJ (2006) Identification of a biomarker for sleep drive in flies and humans. Proc Natl Acad Sci USA 103(52):19913–19918CrossRefPubMedGoogle Scholar
  75. 75.
    Shaw P (2003) Awakening to the behavioral analysis of sleep in Drosophila. J Biol Rhythms 18(1):4–11CrossRefPubMedGoogle Scholar
  76. 76.
    Shaw PJ, Tononi G, Greenspan RJ, Robinson DF (2002) Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 417(6886):287–291CrossRefPubMedGoogle Scholar
  77. 77.
    Sherrington R, Rogaev EI, Liang Y et al (1995) Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375(6534):754–760CrossRefPubMedGoogle Scholar
  78. 78.
    Sitbon G, Khemiss F, Boulanger Y (1982) Effects of total pan-createctomy and amino-acid treatment on plasma amino-acids and glucose in the goose. J Physiol (Paris) 78(3):258–265Google Scholar
  79. 79.
    Song YH (2005) Drosophila melanogaster: a model for the study of DNA damage checkpoint response. Mol Cells 19(2):167–179PubMedGoogle Scholar
  80. 80.
    Soubry A, van Hengel J, Parthoens E et al (2005) Expression and nuclear location of the transcriptional repressor Kaiso is regulated by the tumor microenvironment. Cancer Res 65(6):2224–2233CrossRefPubMedGoogle Scholar
  81. 81.
    Spiegel K, Knutson K, Leproult R, Tasali E, Van Cauter E (2005) Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol 99(5):2008–2019CrossRefPubMedGoogle Scholar
  82. 82.
    Stevaux O, Dimova D, Frolov MV et al (2002) Distinct mechanisms of E2F regulation by Drosophila RBF1 and RBF2. Embo J 21(18):4927–4937CrossRefPubMedGoogle Scholar
  83. 83.
    St John MA, Tao W, Fei X et al (1999) Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction. Nat Genet 21(2):182–186CrossRefGoogle Scholar
  84. 84.
    Struhl G, Greenwald I (1999) Presenilin is required for activity and nuclear access of Notch in Drosophila. Nature 398(6727):522–525CrossRefPubMedGoogle Scholar
  85. 85.
    Tapon N (2003) Modeling transformation and metastasis in Drosophila. Cancer Cell 4(5):333–335CrossRefPubMedGoogle Scholar
  86. 86.
    Tapon N, Ito N, Dickson BJ, Treisman JE, Hariharan IK (2001) The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105(3):345–355CrossRefPubMedGoogle Scholar
  87. 87.
    Tepass U (2002) Adherens junctions: new insight into assembly, modulation and function. Bioessays 24(8):690–695CrossRefPubMedGoogle Scholar
  88. 88.
    Theodosiou NA, Xu T (1998) Use of FLP/FRT system to study Drosophila development. Methods 14(4):355–365CrossRefPubMedGoogle Scholar
  89. 89.
    Vidal M, Cagan RL (2006) Drosophila models for cancer research. Curr Opin Genet Dev 16(1):10–16CrossRefPubMedGoogle Scholar
  90. 90.
    Vidal M, Wells S, Ryan A, Cagan R (2005) ZD6474 suppresses oncogenic RET isoforms in a Drosophila model for type 2 multiple endocrine neoplasia syndromes and papillary thyroid carcinoma. Cancer Res 65(9):3538–3541CrossRefPubMedGoogle Scholar
  91. 91.
    Vidal M, Larson DE, Cagan RL (2006) Csk-deficient boundary cells are eliminated from normal Drosophila epi-thelia by exclusion, migration, and apoptosis. Dev Cell 10(1):33–44CrossRefPubMedGoogle Scholar
  92. 92.
    Wang ZB, Liu YQ, Cui YF (2005) Pathways to caspase activation. Cell Biol Int 29(7):489–496CrossRefPubMedGoogle Scholar
  93. 93.
    Wessells RJ, Bodmer R (2004) Screening assays for heart function mutants in Drosophila. Biotechniques 37(1):58– 60 62, 64 passimPubMedGoogle Scholar
  94. 94.
    Wessells RJ, Fitzgerald E, Cypser JR, Tatar M, Bodmer R (2004) Insulin regulation of heart function in aging fruit flies. Nat Genet 36(12):1275–1281CrossRefPubMedGoogle Scholar
  95. 95.
    Whitworth AJ, Wes PD, Pallanck LJ (2006) Drosophila models pioneer a new approach to drug discovery for Parkinson's disease. Drug Discov Today 11(3–4):119–126CrossRefPubMedGoogle Scholar
  96. 96.
    Wolf FW, Heberlein U (2003) Invertebrate models of drug abuse. J Neurobiol 54(1):161–178CrossRefPubMedGoogle Scholar
  97. 97.
    Woodhouse EC, Liotta LA (2004) Drosophila invasive tumors: a model for understanding metastasis. Cell Cycle 3(1):38–40PubMedGoogle Scholar
  98. 98.
    Yang Y, Hua X (2007) In search of tumor suppressing functions of menin. Mol Cell Endocrinol 265–266:34–41CrossRefPubMedGoogle Scholar
  99. 99.
    Ye Y, Lukinova N, Fortini ME (1999) Neurogenic pheno-types and altered Notch processing in Drosophila Presenilin mutants. Nature 398(6727):525–529CrossRefPubMedGoogle Scholar
  100. 100.
    Zangemeister-Wittke U, Simon HU (2004) An IAP in action: the multiple roles of survivin in differentiation, immunity and malignancy. Cell Cycle 3(9):1121–1123PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2010

Authors and Affiliations

  • Ruth Johnson
    • 1
  • Ross Cagan
    • 2
  1. 1.Department of Molecular, Cell and Developmental BiologyMount Sinai School of Medicine 1 Gustave L. Levy PlaceNew YorkUSA
  2. 2.Department of Developmental and Regenerative BiologyMount Sinai School of MedicineNew YorkUSA

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