Drosophila, the golden bug, emerges as a tool for human genetics

Nature Reviews Genetics

Volumn 6, Issue 1, 2005, Pages 9-23

  Bier, Ethan ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANDROGEN RECEPTOR; CELL NUCLEUS RECEPTOR; CHAPERONIN; CYCLINE; FIBROBLAST GROWTH FACTOR RECEPTOR; GAMMA SECRETASE; GENE PRODUCT; MICROTUBULE PROTEIN; NOTCH RECEPTOR; PROTEIN TYROSINE KINASE; RAPAMYCIN; TATA BINDING PROTEIN; TRANSCRIPTION FACTOR; UBIQUITIN PROTEIN LIGASE;

ALZHEIMER DISEASE; AUDITORY SYSTEM; CAENORHABDITIS ELEGANS; CANCER; CARDIOVASCULAR DISEASE; CELL CYCLE; DEVELOPMENTAL DISORDER; DROSOPHILA MELANOGASTER; EPISTASIS; FRAGILE X SYNDROME; GENE FUNCTION; GENE LINKAGE DISEQUILIBRIUM; GENE MUTATION; GENETIC TRAIT; HAPLOTYPE; HUMAN GENETICS; IMMUNE SYSTEM; METABOLIC DISORDER; METASTASIS; NEUROLOGIC DISEASE; NONHUMAN; PARKINSON DISEASE; PRIORITY JOURNAL; REVIEW; SEQUENCE HOMOLOGY; SIGNAL TRANSDUCTION; STORAGE DISEASE; TERATOLOGY; VISUAL SYSTEM;

ANIMALS; DEVELOPMENTAL DISABILITIES; DROSOPHILA MELANOGASTER; GENES, INSECT; GENETICS, MEDICAL; HUMANS; INFANT, NEWBORN; MODELS, ANIMAL; NEOPLASMS; NERVOUS SYSTEM DISEASES; SIGNAL TRANSDUCTION;

CAENORHABDITIS; CAENORHABDITIS ELEGANS; DROSOPHILA MELANOGASTER; MELANOGASTER;

EID: 10644276290     PISSN: 14710056     EISSN: None     Source Type: Journal    
DOI: 10.1038/nrg1503     Document Type: Review

References (187)

1. Reiter, L. T., Potocki, L., Chien, S., Gribskov, M. & Bier, E. A systematic analysis of human disease-associated gene sequences in Drosophila melanogaster. Genome Res. 11, 1114-1125 (2001). This systematic cross-genomic analysis of human disease homologues in D. melanogaster revealed that 75% of human disease genes, covering a broad range of disorders, have homologues in flies.
2. Chien, S., Reiter, L. T., Bier, E, & Gribskov, M. Homophila: human disease gene cognates in Drosophila. Nucleic Acids Res. 30, 149-151 (2002).
3. Adams, M. D. et al. The genome sequence of Drosophila melanogaster. Science 287, 2185-2195 (2000).
4. Fortini, M. E., Skupski, M. P., Boguski, M. S. & Hariharan, I. K. A survey of human disease gene counterparts in the Drosophila genome. J. Cell Biol. 150, F23-30 (2000).
5. Inlow, J. K. & Restifo, L. L. Molecular and comparative genetics of mental retardation. Genetics 166, 835-881 (2004).
6. Bier, E. & McGinnis, W. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 25-45 (Oxford Univ. Press, New York, 2004).
7. Jiang, J., Kosman, D., Ip, Y. T. & Levine, M. The dorsal morphogen gradient regulates the mesoderm determinant twist in early Drosophila embryos. Genes Dev. 5, 1881-1891 (1991).
8. Kosman, D., Ip, Y. T., Levine, M. & Arora, K. Establishment of the mesoderm-neuroectoderm boundary in the Drosophila embryo. Science 254, 118-122 (1991).
9. Leptin, M. twist and snail as positwe and negative regulators during Drosophila mesoderm development. Genes Dev. 5, 1568-1576 (1991).
10. Rao, Y., Vaessin, H., Jan, L. Y. & Jan, Y. N. Neuroectoderm in Drosophila embryos is dependent on the mesoderm for positioning but not for formation. Genes Dev. 5, 1577-1588 (1991).
11. Ray, R. P., Arora, K., Nusslein-Volhard, C. & Gelbart, W. M. The control of cell fate along the dorsal-ventral axis of the Drosophila embryo. Development 113, 35-54 (1991).
12. Beiman, M., Shilo, B. Z. & Volk, T. Heartless, a Drosophila FGF receptor homolog, is essential for cell migration and establishment of several mesodermal lineages. Genes Dev. 10, 2993-3002 (1996).
13. Gisselbrecht, S., Skeath, J. B., Doe, C. Q. & Michelson, A. M. heartless encodes a fibroblast growth factor receptor (DFR1/DFGF-R2) involved in the directional migration of early mesodermal cells in the Drosophila embryo. Genes Dev. 10, 3003-3017 (1996).
14. Rice, D. P. et al. Integration of FGF and TWIST in calvarial bone and suture development. Development 127, 1845-1855 (2000).
15. Sosic, D., Richardson, J. A., Yu, K., Omitz, D. M. & Olson, E. N. Twist regulates cytokine gene expression through a negative feedback loop that represses NF-κB activity. Cell 112, 169-180 (2003).
16. Ip, Y. T., Park, R. E., Kosman, D., Yazdanbakhsh, K. & Levine, M. dorsal-twist interactions establish snail expression in the presumptive mesoderm of the Drosophila embryo. Genes Dev, 6, 1518-1530, (1992).
17. Irvine, K. D. & Vogt, T. F. Dorsal-ventral signaling in limb development. Curr. Opin. Cell Biol. 9, 867-876 (1997).
18. Wu, J. Y. & Rao, Y. Fringe: defining borders by regulating the Notch pathway. Curr. Opin. Neurobiol. 9, 537-543 (1999).
19. Bridges, C. B. & Morgan, T. H. The third-chromosome group of mutant characters in Drosophila melanogaster Carnegie Inst. Washington Publ. 327, 197-201 (1923).
20. Kusumi, K. et al. The mouse pudgy mutation disrupts Delta homologue Dll3 and initiation of early somite boundaries. Nature Genet. 19, 274-278 (1998).
21. Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377-381 (1998).
22. Zhang, N. & Gridley, T. Defects in somite formation in lunatic fnnge-deficient mice. Nature 394, 374-377 (1998).
23. Li, L. et al. Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1. Nature Genet. 16, 243-251 (1997).
24. Oda, T. et al. Mutations in the human Jagged1 gene are responsible for Alagille syndrome. Nature Genet. 16, 235-242 (1997).
25. Bulman, M. P. et al. Mutations in the human Delta homologue, DLL3, cause axial skeletal defects in spondylocostal dysostosis. Nature Genet. 24, 438-441 (2000). Showed that the human DLL3 gene is mutated in individuals with spondylocostal dysostosis, which is phenotypically similar to loss of Dll3 function in the pudgy mouse mutant.
26. Bodai, L., Pallos, J., Thompson, L. M. & Marsh, J. L. Altered protein acetylation in potyglutamine diseases. Curr. Med. Chem. 10, 2577-2587 (2003).
27. Bonini, N. M. & Fortini, M. E. Human neurodegenerative disease modeling using Drosophila. Annu. Rev. Neurosci. 26, 627-656 (2003).
28. Driscoli, M. & Gerstbrein, B. Dying for a cause: invertebrate genetics takes on human neurodegeneration. Nature Rev. Genet 4, 181-194 (2003).
29. Muqit, M. M. & Feany, M. B. Modelling neurodegenerative diseases in Drosophila: a fruitful approach? Nature Rev. Neurosci. 3, 237-243 (2002).
30. Shulman, J. M., Shulman, L. M., Weiner, W. J. & Feany, M. B. From fruit fly to bedside: translating lessons from Drosophila models of neurodegenerative disease. Curr. Opin. Neurol. 16, 443-449 (2003).
31. Rubinsztein, D. C. Lessons from animal models of Huntington's disease. Trends Genet. 18, 202-209 (2002).
32. Ghosh, S. & Feany, M. B. Comparison of pathways controlling toxicity in the eye and brain in Drosophila models of human neurodegenerative diseases. Hum. Mol. Genet 13, 2011-2018 (2004).
33. Warrick, J. M. et al. Suppression of potyglutamine-mediated neurodegeneration in Drosophila by the molecular chaperone HSP70. Wafure Genet 23, 425-428 (1999). Showed that human HSP70 could suppress the effect of polyglutamine-mediated retinal degeneration in flies, which was also shown subsequently to be the case in mice.
34. Kazemi-Esfarjani, P. & Benzer, S. Genetic suppression of polyglutamine toxicity in Drosophila. Science 287, 1837-1840 (2000).
35. Fernandez-Funez, P. et al. Identification of genes that modify ataxin-1-induced neurodegeneration. Nature 408, 101-106 (2000).
36. Steffan, J. S. et al. Histone deacetylase inhibitors arrest polyglutamine-dependent neurodegeneration in Drosophila. Nature 413, 739-743 (2001).
37. Shulman, J. M. & Feany, M. B. Genetic modifiers of tauopathy in Drosophila. Genetics 165, 1233-1242 (2003).
38. Cummings, C. J. et al. Chaperone suppression of aggregation and altered subcellular proteasome localization imply protein misfolding in SCA1. Nature Genet. 19, 148-154 (1998).
39. Cummings, C. J. et al. Over-expression of inducible HSP70 chaperone suppresses neuropathology and improves motor function in SCA1 mice. Hum. Mol. Genet. 10, 1511-1518 (2001).
40. Hay, D. G. et al. Progressive decrease in chaperone protein levels in a mouse model of Huntington's disease and induction of stress proteins as a therapeutic approach. Hum. Mol. Genet. 13, 1389-1405 (2004).
41. Hockly, E. et al. Suberoylanilide hydroxamic acid, a histone deacetylase inhibitor, ameliorates motor deficits in a mouse model of Huntington's disease. Proc. Natl. Acad. Sci. USA 100, 2041-2046 (2003).
42. Mutsuddi, M., Marshall, C. M., Benzow, K. A., Koob, M. D. & Rebay, I. The spinocerebellar ataxia 8 noncoding RNA causes neurodegeneration and associates with staufen in Drosophila. Curr. Biol. 14, 302-308 (2004).
43. Auluck, P. K. & Bonini, N. M. Pharmacological prevention of Parkinson disease in Drosophila. Nature Med. 8, 1185-1186 (2002).
44. Maroteaux, L., Campanelli, J. T. & Scheller, R. H. Synuclein: a neuron-specific protein iocaieed to the nucleus and presynaptic nerve terminal. J. Neurosci. 8, 2804-2815 (1988).
45. Spillantini, M. G. et al. α-synuclein in Lewy bodies. Nature 388, 839-840 (1997).
46. Feany, M. B. & Bender, W. W. A Drosophila model of Parkinson's disease. Nature 404, 394-398 (2000). Showed that mis-expression of mutant, but not normal, forms of human α-synuclein in flies causes phenotypes similar to those observed in Parkinson disease, including loss of dopaminergic neurons and the formation of filamentous intraneuronal inclusions that are reminiscent of Lewy bodies.
47. Shimura, H. et al. Familial Parkinson disease gene product, parkin, is a ubiquitin-protein ligase. Nature Genet. 25, 302-305 (2000).
48. Shimura, H. et al. Ubiquitination of a new form of α-synuclein by parkin from human brain: implications for Parkinson's disease. Science 293, 263-269 (2001).
49. Pesah, Y. et al. Drosophila parkin mutants have decreased mass and cell size and increased sensitivity to oxygen radical stress. Development 131, 2183-2194 (2004).
50. Haywood, A. F. & Staveley, B. E. Parkin counteracts symptoms in a Drosophila model of Parkinson's disease. BMC Neurosci. 5, 14 (2004).
51. Yang, Y., Nishimura, I., Imai, Y., Takahashi, R. & Lu, B. Parkin suppresses dopaminergic neuron-selective neurotoxicity induced by Pael-R in Drosophila. Neuron 37, 911-924 (2003).
52. Levy-Lahad, E. et al. A familial Alzheimer's disease locus on chromosome 1. Science 269, 970-973 (1995).
53. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754-760 (1995).
54. Kopan, R. & Goate, A. A common enzyme connects Notch signaling and Alzheimer's disease. Genes Dev. 14, 2799-2806 (2000).
55. Chartier-Harlin, M. C. et al. Early-onset Alzheimer's disease caused by mutations at codon 717 of the β-amyloid precursor protein gene. Nature 353, 844-846 (1991).
56. Murrell, J., Farlow, M., Ghetti, B. & Benson, M. D. A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease. Science 254, 97-99 (1991).
57. Goate, A. et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease. Nature 349, 704-706 (1991).
58. Leissring, M. A. et al. A physiologic signaling role for the α-secretase-derived intracellular fragment of APR Proc. Natl. Acad. Sci. USA 99, 4697-702 (2002).
59. Kimberty, W. T., Zheng, J. B., Guenette, S. Y. & Selkoe, D. J. The intracellular domain of the β-amyloid precursor protein is stabilized by Fe65 and translocates to the nucleus in a Notch-like manner. J. Biol. Chem. 276, 40288-40292 (2001).
60. Gao, Y. & Pimplikar, S. W. The α-secretase-cleaved C-terminal fragment of amyloid precursor protein mediates signaling to the nucleus. Proc. Natl. Acad. Sci. USA 98, 14979-14984 (2001).
61. Cupers, P., Orlans, I., Craessaerts, K., Annaert, W. & De Strooper, B. The amyloid precursor protein (APP)-cytoplasmic fragment generated by cc-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture. J. Neurochem, 78, 1168-1178 (2001).
62. Cao, X. & Sudhof, T. C. A transcriptionally active complex of APP with Fe65 and histone acetyltransferase Tip60. Science 293, 115-120 (2001).
63. Kamal, A., Almenar-Queralt, A., LeBlanc, J. F., Roberts, E. A. & Goldstein, L. S. Kinesin-mediated axonal transport of a membrane compartment containing α-secretase and presenilin-1 requires APP. Nature 414, 643-648 (2001).
64. Gunawardena, S. & Goldstein, L. S. Disruption of axonal transport and neuronal viability by amyloid precursor protein mutations in Drosophila. Neuron 32, 389-401 (2001).
65. White, A. R. et al. Contrasting, species-dependent modulation of copper-mediated neurotoxicity by the Alzheimer's disease amyloid precursor protein. J. Neurosci. 22, 365-376 (2002).
66. Kopan, R. & Goate, A. Aph-2/Nicastrin: an essential component of α-secretase and regulator of Notch signaling and Presenilin localization. Neuron 33, 321-324 (2002).
67. Francis, R. et al. aph-1 and pen-2 are required for Notch pathway signaling, α-secretase cleavage of βAPR and presenilin protein accumulation. Dev. Cell 3, 85-97 (2002).
68. Lopez-Schier, H. & St. Johnston, D. Drosophila nicastrin is essential for the intramembranous cleavage of Notch. Dev. Cell. 2, 79-89 (2002).
69. Hu, Y., Ye, Y. & Fortini, M. E. Nicastrin is required for γ-secretase cleavage of the Drosophila Notch receptor. Dev. Cell 2, 69-78 (2002).
70. Chung, H. M. & Struhl, G. Nicastrin is required for Presenilin-mediated transmembrane cleavage in Drosophila. Nature Cell Biol. 3, 1129-1132 (2001).
71. Yu, G. et al. Nicastrin modulates presenilin-mediated Notch/glp-1 signal transduction and βAPP processing. Nature 407, 48-54 (2000).
72. Siomi, H., Ishizuka, A. & Siomi, M. C. RNA interference: a new mechanism by which FMRP acts in the normal brain? What can Drosophila teach us? Ment Retard. Dev. Disabil. Res. Rev. 10, 68-74 (2004).
73. Zhang, Y. Q. et al. Drosophila fragile X-related gene regulates the MAP1 B homolog Futsch to control synaptic structure and function. Cell 107, 591-603 (2001).
74. Lee, A. et al. Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 130, 5543-5552 (2003).
75. Ishizuka, A., Siomi, M. C. & Siomi, H. A Drosophila fragile X protein interacts with components of RNAi and ribosomal proteins. Genes DeK 16, 2497-2508 (2002). Makes the link between the gene mutated in Fragile-X syndrome - FMR1- and the RNAi pathway by showing that the D. melanogaster FMR1 homologue (Fmr1) is present in a complex with several essential components of the RNAi pathway such as AGO1, p68 RNA helicase and Dicer.
76. Jin, P. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nature Neurosci. 7, 113-117 (2004).
77. Jin, R et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 39, 739-747 (2003).
78. Simon, M. A., Bowtell, D. D., Dodson, G.S., Laverty,T. R. & Rubin, G. M. Ras1 and a putative guanine nucleotide exchange factor perform crucial steps in signaling by the Sevenless protein tyrosine kinase. Cell 67, 701-716 (1991).
79. Dickson, B. J., van der Straten, A., Dominguez, M. & Hafen, E. Mutations modulating Raf signaling in Drosophila eye development. Genetics 142, 163-171 (1996).
80. Margolis, B. & Skolnik, E. Y. Actuation of Ras by receptor tyrosine kinases. J. Am. Soc. Nephrol. 5, 1288-1299 (1994).
81. Han, M. & Sternberg, R W. let-60, a gene that specifies cell fates during C. elegans vulval induction, encodes a Ras protein. Cell 63, 921-931 (1990).
82. Aroian, R. V., Koga, M., Mendel, J. E., Ohshima, Y. & Sternberg, P. W. The let-23 gene necessary for Caenorhabditis elegans vulval induction encodes a tyrosine kinase of the EGF receptor subfamily. Nature 348, 693-699 (1990).
83. Hill, R. J. & Sternberg, P. W. The gene lin-3 encodes an inductive signal for vulval development in C. elegans. Nature 358, 470-476 (1992).
84. Han, M., Golden, A., Han, Y. & Sternberg, R W. C. elegans lin-45 Raf gene participates in let-60 Ras-stimulated vulval differentiation. Nature 363, 133-140 (1993).
85. Huang, L. S., Tzou, P. & Sternberg, P. W. The lin-15 locus encodes two negative regulators of Caenorhabditis elegans vulval development. Mol. Biol. Cell 5, 395-411 (1994).
86. Pan, D., Dong, J., Zharig, Y. & Gao, X. Tuberous sclerosis complex: from Drosophila to human disease. Trends Cell Biol. 14, 78-85 (2004).
87. Gao, X. & Pan, D. TSC1 and TSC2 tumor suppressors antagonize insulin signaling in cell growth. Genes Dev. 15, 1383-1392 (2001).
88. Potter, C. J., Huang, H. & Xu, T. Drosophila Tsc1 functions with Tsc2 to antagonize insulin signaling in regulating cell growth, cell proliferation, and organ size. Cell 105, 357-368 (2001).
89. Tapon, N., Ito, N., Dickson, B. J., Treisman, J. E. & Hariharan, I. K. The Drosophila tuberous sclerosis complex gene homologs restrict cell growth and cell proliferation. Cell 105, 345-355 (2001).
90. Kamada, Y., Sekito, T. & Ohsumi, Y. Autophagy in yeast: a TOR-mediated response to nutrient starvation. Curr. Top. Microbiol. Immunol. 279, 73-84 (2004).
91. Neufeld, T. P. Body building: regulation of shape and size by PI3K/TOR signaling during development. Mech. Dev. 120, 1283-1296 (2003).
92. Saucedo, L. J. & Edgar, B. A. Why size matters: altering cell size. Curr. Opin. Genet. Dev. 12, 565-571 (2002).
93. Sutcliffe, J. E., Korenjak, M. & Brehm, A. Tumour suppressors-a fly's perspective. Eur. J. Cancer 39, 1355-1362 (2003).
94. Justice, R. W., Zilian, O., Woods, D. F., Noll, M. & Bryant, P. J. The Drosophila tumor suppressor gene warts encodes a homolog of human myotonic dystrophy kinase and is required for the control of cell shape and proliferation. Genes Dev. 9, 534-546 (1995).
95. Xu, T., Wang, W., Zhang, S., Stewart, R. A. & Yu, W. Identifying tumor suppressors in genetic mosaics: the Dmsophila lats gene encodes a putative protein kinase. Development 121, 1053-1063 (1995).
96. Tapon, N. et al. salvador promotes both cell cycle exit and apoptosis in Drosophila and is mutated in human cancer cell lines. Cell 110, 467-478 (2002). Identified mutations in the D. melanogaster salvador gene that resulted in tissue overgrowth and found that the human homologue of this gene was mutated in cancer cell lines.
97. Harvey, K. F., Pfleger, C. M. & Hariharan, I. K. The Drosophila Mst ortholog, hippo, restricts growth and cell proliferation and promotes apoptosis. Cell 114, 457-467 (2003).
98. Starz-Gaiano, M. & Montell, D. J. Genes that drive invasion and migration in Drosophila. Curr. Opin. Genet. Dev. 14, 86-91 (2004).
99. Pagliarini, R. A. & Xu, T. A genetic screen in Drosophila for metastatic behavior. Science 302, 1227-1231 (2003). Showed that mutations in the D. melanogaster scribbled gene, which is involved in maintaining cell polarity, can cause cells that express an activated oncogenic form of RAS to metastasize. See also reference 96.
100. Brumby, A. M. & Richardson, H. E. scribble mutants cooperate with oncogenic Ras or Notch to cause neoplastic overgrowth in Drosophila. EMBO J. 22, 5769-5779 (2003).
101. Fang, P. et al. The spectrum of mutations in UBE3A causing Angelman syndrome. Hum. Mol. Genet. 8, 129-135 (1999).
102. Kishino, T., Lalande, M. & Wagstaff, J. UBE3A/E6-AP mutations cause Angelman syndrome. Nature Genet. 15, 70-73 (1997).
103. Matsuura, T. et al. De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome. Nature Genet. 15, 74-77 (1997).
104. Netto, L. E. S., Chae, H. Z., Kang, S. W., Rhee, S. G. & Stadtman, E. R. Removal of hydrogen peroxide by thiol-specific antioxidant enzyme (TSA) is involved with its antioxidant properties. TSA possesses thiol peroxidase activity. J. Biol. Chem. 271, 15315-15321 (1996).
105. Lim, Y. S. et al. Removals of hydrogen peroxide and hydroxyl radical by thiol-specific antioxidant protein as a possible role in vivo. Biochem. Biophys. Res. Commun. 192, 273-280 (1993).
106. 2 mixed-function oxidation system. J. Biol. Chem. 263, 4704-4711 (1988).
107. Znou, Y. et al. Presenilin-1 protects against neuronal apoptosis caused by its interacting protein PAG. Neurobiol. Dis. 9, 126-138 (2002).
108. Bejjani, B. A. et al. Mutations in CYP1B1, the gene for cytochrome P4501B1, are the predominant cause of primary congenital glaucoma in Saudi Arabia. Am. J. Hum. Genet. 62, 325-333 (1998).
109. Stoilov, I., Akarsu, A. N. & Sarfarazi, M. Identification of three different truncating mutations in cytochrome P4501B1 (CYP1B1) as the principal cause of primary congenital glaucoma (Buphthalmos) in families linked to the GLC3A locus on chromosome 2p21. Hum. Mol. Genet. 6, 641-647 (1997).
110. Gibbs, R. A. et al. The International HapMap Project. Nature 426, 789-796 (2003). This paper by the International HapMap Project consortium defines the goals and motivation for determining patterns of sequence variation in the human genome, which should provide crucial information for identifying genes involved in polygenic disorders.
111. Aebi, M. & Hennet, T. Congenital disorders of glycosylation: genetic model systems lead the way. Trends Cell Biol. 11, 136-141 (2001).
112. Imbach, T. et al. A mutation in the human ortholog of the Saccharomyces cerevisiae ALG6 gene causes carbohydrate-deficient glycoprotein syndrome type-Ic. Proc. Natl. Acad. Sci. USA 96, 6982-6987(1999).
113. Imbach, T. et al. Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie. J. Clin. Invest. 105, 233-239 (2000).
114. Grubenmann, C. E. et al. Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik. Hum. Mol. Genet. 13, 535-542(2004).
115. Westphal, V. et al. A frequent mild mutation in ALG6 may exacerbate the clinical severity of patients with congenital disorder of glycosylation Ia (CDG-Ia) caused by phosphomannomutase deficiency. Hum. Mol. Genet. 11, 599-604 (2002).
116. Bodmer, R. Heart development in Drosophila and its relationship to vertebrate systems. Trends Cardiovasc. Med. 5, 21-28 (1995).
117. Wessells, R. J. & Bodmer, R. Screening assays for heart function mutants in Drosophila. Biotechniques 37, 58-60, 62, 64 passim (2004).
118. Wessels, R. J., Fitzgerald, E., Cypser, J. R., Tatar, M. & Bodmer, R. Insulin regulation of heart function in aging fruit flies. Nature Genetics (in the press).
119. Kosman, D. et al. Multiplex detection of RNA expression in Drosophila embryos. Science 305, 846 (2004).
120. Elefant, F. & Palter, K. B. Tissue-specific expression of dominant negative mutant Drosophila HSC70 causes developmental defects and lethality. Mol. Biol. Cell 10, 2101-2017 (1999).
121. Pinsky, L. et al. Androgen resistance due to mutation of the androgen receptor. Clin. Invest. Med. 15, 456-472 (1992).
122. Buchanan, R. L. & Benzer, S. Defective glia in the Drosophila bran degeneration mutant drop-dead. Neuron 10, 839-850 (1993).
123. Rogina, B., Benzer, S. & Helfand, S. L. Drosophila drop-dead mutations accelerate the time course of age-related markers. Proc. Natl. Acad. Sci. USA 94, 6303-6306 (1997).
124. Zinsmaier, K. E., Eberle, K. K., Buchner, E., Walter, N. & Benzer, S. Paralysis and early death in cysteine string protein mutants of Drosophila. Science 263, 977-980 (1994).
125. Kretzschmar, D., Hasan, G., Sharma, S., Heisenberg, M. & Benzer, S. The Swiss cheese mutant causes glial hyperwrapping and brain degeneration in Drosophila. J. Neurosci. 17, 7425-7432 (1997).
126. Lin, Y. J., Seroude, L. & Benzer, S. Extended life-span and stress resistance in the Drosophila mutant methuselah. Science 282, 943-946 (1998).
127. Tatar, M. et al. A mutant Drosophila insulin receptor homolog that extends life-span and impairs neuroendocrine function. Science 292, 107-110 (2001).
128. Tatar, M., Bartke, A. & Antebi, A. The endocrine regulation of aging by insulin-like signals. Science 299, 1346-1351 (2003).
129. Tatar, M. Unearthing loci that influence life span. Sci. Aging Knowledge Environ. 2003, PE5 (2003).
130. Antebi, A. Inside insulin signaling, communication is key to long life. Sci. Aging Knowledge Environ. 2004, PE25 (2004).
131. Kapahi, P et al. Regulation of lifespan in Drosophila by modulation of genes in the TOR signaling pathway. Curr. Biol. 14, 885-890 (2004).
132. Tower, J. There's a problem in the furnace. Sci. Aging Knowledge Environ. 2004, PE1 (2004).
133. Jabs, E. M. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 401-409 (Oxford Univ. Press, New York, 2004).
134. Lai, E. C., Deblandre, G. A., Kintner, C. & Rubin, G. M. Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of Delta, Dev. Cell 1, 783-794 (2001).
135. Fryer, C. J., Lamar, E., Turbachova, I., Kintner, C. & Jones, K. A. Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex. Genes Dev. 16, 1397-1411 (2002).
136. Saga, Y. & Takeda, H. The making of the somite: molecular events in vertebrate segmentation. Nature Rev. Genet. 2, 835-845 (2001).
137. Aulehla, A. & Herrmann, B. G. Segmentation in vertebrates: clock and gradient finally joined. Genes Dev. 18, 2060-2067 (2004).
138. Bessho, Y. & Kageyama, R. Oscillations, clocks and segmentation. Curr. Opin. Genet Dev. 13, 379-384 (2003).
139. Kim, H. J. & Bar-Sagi, D. Modulation of signalling by Sprouty: a developing story. Nature Rev. Mol. Cell Biol. 5, 441-450 (2004).
140. Muragaki, Y, Mundlos, S., Upton, J. & Olsen, B. R. Altered growth and branching patterns in synpolydactyly caused by mutations in HOXD13. Science 272, 548-551 (1996).
141. Akarsu, A. N., Stoilov, I., Yilmaz, E., Sayli, B. S. & Sarfarazi, M. Genomic structure of HOXD13 gene: a nine polyalanine duplication causes synpolydactyly in two unrelated families. Hum. Mol. Genet. 5, 945-952 (1996).
142. Goodman, F. R. et al. Synpolydactyly phenotypes correlate with size of expansions in HOXD13 polyalanine tract. Proc. Natl. Acad. Sci. USA 94, 7458-7463 (1997).
143. Del Campo, M. et al. Monodactylous limbs and abnormal genitalia are associated with hemizygosity for the human 2q31 region that includes the HOXD cluster. Am. J. Hum. Genet. 65, 104-110 (1999).
144. Goodman, F. et al. Deletions in HOXD13 segregate with an identical, novel foot malformation in two unrelated families. Am. J. Hum. Genet. 63, 992-1000 (1998).
145. Goodman, F. R. et al. Novel HOXA13 mutations and the phenotypic spectrum of Hand-Foot-Genital syndrome. Am. J. Hum. Genet. 63S, A18 (1998).
146. Goodman, F. R. et al. Novel HOXA13 mutations and the phenotypic spectrum of hand-foot-genital syndrome. Am. J. Hum. Genet 67, 197-202 (2000).
147. Mortlock, D. R. & Innis, J. W. Mutation of HOXA13 in hand-foot-genital syndrome. Nature Genet. 15, 179-180 (1997).
148. Mortlock, D. P., Post, L. C. & Innis, J. W. The molecular basis of hypodactyly (Hd): a deletion in Hoxa 13 leads to arrest of digital arch formation. Nature Genet. 13, 284-289 (1996). The first study to show that a reduction in Hox gene function leads to digit malformation in vertebrates
149. Devriendt, K. et al. Haploinsuffidency of the HOXA gene cluster, in a patient with hand-foot-genital syndrome, velopharyngeal insufficiency, and persistent patent Ductus botalli. Am. J. Hum. Genet. 65, 249-251 (1999).
150. Czerny, T. et al. twin of eyeless, a second Pax-6 gene of Drosophila, acts upstream of eyeless in the control of eye development. Mol. Cell 3, 297-307 (1999).
151. Jiao, R. et al. Headless flies generated by developmental pathway interference. Development 128, 3307-3319 (2001).
152. Quiring, R., Walldorf, U., Kloter, U. & Gehring, W. J. Homology of the eyeless gene of Drosophila to the small eye gene in mice and aniridia in humans. Science 255, 785-789 (1994).
153. van Heningen, V. & Willlamson, K. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 649-657 (Oxford Univ. Press, New York, 2004).
154. Kohlhase, J. SALL1 mutations in Townes-Brocks syndrome and related disorders. Hum. Mutat. 16, 460-466 (2000).
155. Kohlhase, J. & Engel, W. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 265-271 (Oxford Univ. Press, New York, 2004).
156. Dong, P. D., Dicks, J. S. & Panganiban, G. Distal-less and homothorax regulate multiple targets to pattern the Drosophila antenna. Development 129, 1967-1974 (2002).
157. Cohen, M. M. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 380-400 (Oxford Univ. Press, New York, 2004).
158. Spinner, N. B. & Krantz, I. D. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 461-469 (Oxford Univ. Press, New York, 2004).
159. Turnpenny, P. D. & Kusumi, K. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 470-481 (Oxford Univ. Press, New York, 2004).
160. Prall, O. W., Eiliott, D. A. & Harvey, R. P. Developmental paradigms in heart disease: insights from tinman. Ann. Med. 34, 148-156 (2002).
161. Schott, J. J. et al. Congenital heart disease caused by mutations in the transcription factor NKX2-5. Science 281, 108-111 (1998).
162. Jay, P. Y., Powell, A. J., Sherwood, M, C. & Izumo, S. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A. A.) 607-614 (Oxford Univ. Press, New York, 2004).
163. Garg, V. et al. GATA4 mutations cause human congenital heart defects and reveal an interaction with TBXS. Nature 424, 443-447 (2003).
164. Klinedinst, S. L. & Bodmer, R. Gata factor Pannier is required to establish competence for heart progenitor formation. Development 130, 3027-3038 (2003).
165. Patient, R. K. & McGhee, J. D. The GATA family (vertebrates and invertebrates). Curr. Opin. Genet. Dev. 12, 416-422 (2002).
166. Bamshad, M. J. & Jorde, L. B. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 705-718 (Oxford Univ. Press, New York, 2004).
167. Hamaguchi, T., Yabe, S., Uchiyama, H. & Murakami, R. Drosophila Tbx6-related gene, Dorsocross, mediates high levels of Dpp and Scw signal required for the development of amnioserosa and wing disc primordium. Dev. Biol. 265, 355-368 (2004).
168. Reim, I., Lee, H. H. & Frasch, M. The T-box-encoding Dorsocross genes function in amnioserosa development and the patterning of the dorsolateral germ band downstream of Dpp. Development 130, 3187-3204 (2003).
169. Klewer, S. E., Runyan, R. B. & Erickson, R. P. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 699-704 (Oxford Univ. Press, New York, 2004).
170. Vikkuia, M. et al. Vascular dysmorphogenesis caused by an activating mutation in the receptor tyrosine kinase TIE2. Cell 87, 1181-1190 (1996).
171. Ross, C. A. Polygiutamine pathogenesis: emergence of unifying mechanisms for Huntington's disease and related disorders. Neuron 35, 819-822 (2002).
172. Marsh, J. L., Pallos, J. & Thompson, L. M. Fly models of Huntington's disease. Hum. Mol. Genet. 12 Review issue 2, R187-193 (2003).
173. Bates, G. P. & Hockly, E. Experimental therapeutics in Huntington's disease: are models useful for therapeutic trials? Curr. Opin. Neurol. 16, 465-470 (2003).
174. Gunawardena, S. et al. Disruption of axonal transport by loss othuntingtin or expression of pathogenic polyQ proteins in Drosophila. Neuron 40, 25-40 (2003).
175. de Silva, R. & Farrer, M. Tau neurotoxicity without the lesions: a fly challenges a tangled web. Trends Neurosci. 25, 327-329 (2002).
176. Valente, E. M. et al. Hereditary earty-onset Parkinson's disease caused by mutations in PINK1. Science 304, 1158-1160 (2004).
177. Chiurazzi, P., Neri, G. & Oostra, B. A. Understanding the biological underpinnings of fragile X syndrome. Curr. Opin. Pediatr. 15, 559-566 (2003).
178. Bakker, C. E. & Oostra, B. A. Understanding fragile X syndrome: insights from animal models. Cytogenet. Genome Res. 100, 111-123 (2003).
179. Jiang, Y. H. & Beaudet, A. L. Human disorders of ubiquitination and proteasomal degradation. Curr. Opin. Pediatr. 16, 419-126 (2004).
180. Wagstaff, J. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 823-827 (Oxford Univ. Press, New York, 2004).
181. Rosner, M., Hofer, K., Kubista, M. & Hengstschlager, M. Cell size regulation by the human TSC tumor suppressor proteins depends on PI3K and FKBP38. Oncogene 22, 4786-4798 (2003).
182. Kwiatkowski, D. J. in Molecular Basis of Inborn Errors of Development (eds Epstein C. J., Erikson, R. P. & Wynshaw-Boris, A.) 920-930 (Oxford Univ. Press, New York, 2004).
183. Hengstschlager, M. & Rosner, M. The cell cycle and tuberous sclerosis. Prog. Cell. Cycle Res. 5, 43-48 (2003).
184. Narayanan, V. Tuberous sclerosis complex: genetics to pathogenesis. Pediatr. Neurol. 29, 404-409 (2003).
185. Tapon, N. Modeling transformation and metastasis in Drosophila. Cancer Cell 4, 333-335 (2003).
186. El Ghouzzi, V. et al. Mutations of the TWIST gene in the Saethre-Chotzene syndrome Nature Genet. 15, 42-46 (1997).
187. Sturtevant, MA and Bier, E. Analysis of the genetic hierarchy guiding wing vein development in Drosophila. Development 121, 785-801 (1995).