Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Model organisms

Chemistry-to-gene screens in Caenorhabditis elegans

Nature Reviews Drug Discovery volume 4, pages 321–330 (2005)Cite this article

Key Points

  • The nematode Caenorhabditis elegans has become a widely used model organism in academic and industrial research. This is the result of its ease of cultivation and maintenance, short lifespan, fully sequenced genome, advanced genetic toolkit, complete description of cell lineage, simple nervous system, as well as its suitability for high-throughput genetic and chemical screening.

  • A chemistry-to-gene screen is a forward genetic approach in which mutagenized C. elegans worms are screened for resistance to a particular compound. The resulting mutations are mapped to identify genes underlying resistance.

  • Chemistry-to-gene screens have successfully defined the molecular targets of drugs controlling nematode parasites, such as levamisole, aldicarb, benzimidazoles and ivermectin. They have also revealed targets of human drugs such as nicotine, alcohol and volatile anaesthetics.

  • RNA interference (RNAi) is a reverse genetic approach highly suitable for gene-to-chemistry screens. RNAi has now been refined in C. elegans to the extent that it provides a very tractable, high-throughput tool that has considerable potential to define and validate the genetic basis of drug action.

  • Screens on mutant worms have provided a proof of principle for the use of C. elegans in screening for candidate drugs to treat human diseases.

Abstract

The nematode worm Caenorhabditis elegans is a genetic model organism linked to an impressive portfolio of fundamental discoveries in biology. This free-living nematode, which can be easily and inexpensively grown in the laboratory, is also a natural vehicle for screening for drugs that are active against nematode parasites. Here, we show that chemistry-to-gene screens using this animal model can define targets of antiparasitic drugs, identify novel candidate drug targets and contribute to the discovery of new drugs for treating human diseases.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Chemistry-to-gene screening begins with mutagenesis of worms, usually by exposure to mutagens.
Figure 2: Chemistry-to-gene screens identify drug targets as well as functionally linked genes.
Figure 3: A novel use of chemistry-to-gene screening involves the discovery of phenotype-suppressor genes.

Similar content being viewed by others

References

  1. Chan, M. S. The global burden of intestinal nematode infections — fifty years on. Parasitol. Today 13, 438–443 (1997).

    Article  CAS  PubMed  Google Scholar 

  2. Jasmer, D. P., Goverse, A. & Smant, G. Parasitic nematode interactions with mammals and plants. Annu. Rev. Phytopathol. 41, 245–270 (2003).

    Article  CAS  PubMed  Google Scholar 

  3. Kaplan, R. M. Drug resistance in nematodes of veterinary importance: a status report. Trends Parasitol. 20, 477–481 (2004).

    Article  CAS  PubMed  Google Scholar 

  4. Geary, T. G. & Thompson, D. P. Caenorhabditis elegans: how good a model for veterinary parasites? Vet. Parasitol. 101, 371–386 (2001).

    Article  CAS  PubMed  Google Scholar 

  5. Ankeny, R. A. The natural history of Caenorhabditis elegans research. Nature Rev. Genet. 2, 474–479 (2001).

    Article  CAS  PubMed  Google Scholar 

  6. Sulston, J. E. & Horvitz, H. R. Post-embryonic cell lineages of the nematode, Caenorhabditis elegans. Dev. Biol. 56, 110–156 (1977).

    Article  CAS  PubMed  Google Scholar 

  7. White, J. G., Southgate, E., Thomson, J. N. & Brenner, S. The structure of the ventral nerve cord of Caenorhabditis elegans. Philos. Trans. R. Soc. Lond. B Biol. Sci. 275, 327–348 (1976).

    Article  CAS  PubMed  Google Scholar 

  8. Genome sequence of the nematode C. elegans: a platform for investigating biology. The C. elegans Sequencing Consortium. Science 282, 2012–2018 (1998).

  9. Harris, T. W. et al. WormBase: a multi-species resource for nematode biology and genomics. Nucleic Acids Res. 32, D411–D417 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Jorgensen, E. M. & Mango, S. E. The art and design of genetic screens: Caenorhabditis elegans. Nature Rev. Genet. 3, 356–369 (2002). An outstanding and comprehensive review of all kinds of genetic screens used in conjunction with C. elegans.

    Article  CAS  PubMed  Google Scholar 

  11. Carpenter, A. E. & Sabatini, D. M. Systematic genome-wide screens of gene function. Nature Rev. Genet. 5, 11–22 (2004).

    Article  CAS  PubMed  Google Scholar 

  12. Sulston, J. E. Caenorhabditis elegans: the cell lineage and beyond (Nobel lecture). Chembiochem 4, 688–696 (2003).

    Article  CAS  PubMed  Google Scholar 

  13. Chalfie, M. & Jorgensen, E. M. C. elegans neuroscience: genetics to genome. Trends Genet. 14, 506–512 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Baehrecke, E. H. How death shapes life during development. Nature Rev. Mol. Cell Biol. 3, 779–787 (2002).

    Article  CAS  Google Scholar 

  15. Culetto, E. & Sattelle, D. B. A role for Caenorhabditis elegans in understanding the function and interactions of human disease genes. Hum. Mol. Genet. 9, 869–877 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Driscoll, M. & Gerstbrein, B. Dying for a cause: invertebrate genetics takes on human neurodegeneration. Nature Rev. Genet. 4, 181–194 (2003).

    Article  CAS  PubMed  Google Scholar 

  17. Poulin, G., Nandakumar, R. & Ahringer, J. Genome-wide RNAi screens in Caenorhabditis elegans: impact on cancer research. Oncogene 23, 8340–8345 (2004).

    Article  CAS  PubMed  Google Scholar 

  18. Raymond, V. & Sattelle, D. B. Novel animal-health drug targets from ligand-gated chloride channels. Nature Rev. Drug Discov. 1, 427–436 (2002).

    Article  CAS  Google Scholar 

  19. Chen, N. et al. WormBase: a comprehensive data resource for Caenorhabditis biology and genomics. Nucleic Acids Res. 33, D383–D389 (2005).

    Article  CAS  PubMed  Google Scholar 

  20. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974). The first detailed mutagenesis screen on C. elegans , which reported many viable phenotypes.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Jakubowski, J. & Kornfeld, K. A local, high-density, single-nucleotide polymorphism map used to clone Caenorhabditis elegans cdf-1. Genetics 153, 743–752 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Bessereau, J. L. et al. Mobilization of a Drosophila transposon in the Caenorhabditis elegans germ line. Nature 413, 70–74 (2001).

    Article  CAS  PubMed  Google Scholar 

  23. Martin, E. et al. Identification of 1088 new transposon insertions of Caenorhabditis elegans: a pilot study toward large-scale screens. Genetics 162, 521–524 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Thienpont, D. et al. Tetramisole (R 8299), a new, potent broad spectrum anthelmintic. Nature 209, 1084–1086 (1966).

    Article  CAS  PubMed  Google Scholar 

  25. Lewis, J. A., Wu, C. H., Levine, J. H. & Berg, H. Levamisole-resistant mutants of the nematode Caenorhabditis elegans appear to lack pharmacological acetylcholine receptors. Neuroscience 5, 967–989 (1980).

    Article  CAS  PubMed  Google Scholar 

  26. Harrow, I. D. & Gration, K. A. F. Mode of action of the anthelmintics morantel, pyrantel and levamisole on muscle cell membrane of the nematode Ascaris suum. Pestic. Sci. 16, 662–672 (1985).

    Article  CAS  Google Scholar 

  27. Martin, R. J., Valkanov, M. A., Dale, V. M., Robertson, A. P. & Murray, I. Electrophysiology of Ascaris muscle and anti-nematodal drug action. Parasitology 113, S137–S156 (1996).

    Article  PubMed  Google Scholar 

  28. Lewis, J. A. et al. Cholinergic receptor mutants of the nematode Caenorhabditis elegans. J. Neurosci. 7, 3059–3071 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Fleming, J. T. et al. Caenorhabditis elegans levamisole resistance genes lev-1, unc-29, and unc-38 encode functional acetylcholine receptor subunits. J. Neurosci. 17, 5843–5857 (1997). This paper reports the first cloning of nicotinic receptor subunits targeted by levamisole.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Culetto, E. et al. The Caenorhabditis elegans unc-63 gene encodes a levamisole-sensitive nicotinic acetylcholine receptor α subunit. J. Biol. Chem. 279, 42476–42483 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Towers, P. R. & Sattelle, D. B. The C. elegans lev-8 gene encodes a nicotinic acetylcholine receptor subunit (ACR-13) with roles in egg laying and pharyngeal pumping. J. Neurochem. 93, 1–9 (2005).

    Article  CAS  PubMed  Google Scholar 

  32. Karlin, A. Emerging structure of the nicotinic acetylcholine receptors. Nature Rev. Neurosci. 3, 102–114 (2002).

    Article  CAS  Google Scholar 

  33. Jones, A. K. & Sattelle, D. B. Functional genomics of the nicotinic acetylcholine receptor gene family of the nematode, Caenorhabditis elegans. Bioessays 26, 39–49 (2004).

    Article  CAS  PubMed  Google Scholar 

  34. Richmond, J. E. & Jorgensen, E. M. One GABA and two acetylcholine receptors function at the C. elegans neuromuscular junction. Nature Neurosci. 2, 791–797 (1999). A breakthrough in functional analysis of C. elegans synapses resulting from the application of patch-clamp electrophysiology to body-wall muscle.

    Article  CAS  PubMed  Google Scholar 

  35. Robertson, A. P., Bjorn, H. E. & Martin, R. J. Resistance to levamisole resolved at the single-channel level. FASEB J. 13, 749–760 (1999).

    Article  CAS  PubMed  Google Scholar 

  36. Robertson, A. P., Bjorn, H. E. & Martin, R. J. Pyrantel resistance alters nematode nicotinic acetylcholine receptor single-channel properties. Eur. J. Pharmacol. 394, 1–8 (2000).

    Article  CAS  PubMed  Google Scholar 

  37. Fitzgerald, J. et al. UNCL, the mammalian homologue of UNC-50, is an inner nuclear membrane RNA-binding protein. Brain Res. 877, 110–123 (2000). An elegant demonstration of how a gene first isolated in a C. elegans chemistry-to-gene screen uncovers the function of the corresponding mammalian gene.

    Article  CAS  PubMed  Google Scholar 

  38. Gally, C., Eimer, S., Richmond, J. E. & Bessereau, J. L. A transmembrane protein required for acetylcholine receptor clustering in Caenorhabditis elegans. Nature 431, 578–582 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Maryon, E. B., Coronado, R. & Anderson, P. unc-68 encodes a ryanodine receptor involved in regulating C. elegans body-wall muscle contraction. J. Cell. Biol. 134, 885–893 (1996).

    Article  CAS  PubMed  Google Scholar 

  40. Jenden, D. J. & Fairhurst, A. S. The pharmacology of ryanodine. Pharmacol. Rev. 21, 1–25 (1969).

    CAS  PubMed  Google Scholar 

  41. Benian, G. M., L'Hernault, S. W. & Morris, M. E. Additional sequence complexity in the muscle gene, unc-22, and its encoded protein, twitchin, of Caenorhabditis elegans. Genetics 134, 1097–1104 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Kagawa, H., Takuwa, K. & Sakube, Y. Mutations and expressions of the tropomyosin gene and the troponin C gene of Caenorhabditis elegans. Cell Struct. Funct. 22, 213–218 (1997).

    Article  CAS  PubMed  Google Scholar 

  43. Nguyen, M., Alfonso, A., Johnson, C. D. & Rand, J. B. Caenorhabditis elegans mutants resistant to inhibitors of acetylcholinesterase. Genetics 140, 527–535 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Miller, K. G. et al. A genetic selection for Caenorhabditis elegans synaptic transmission mutants. Proc. Natl Acad. Sci. USA 93, 12593–12598 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Alfonso, A., Grundahl, K., McManus, J. R. & Rand, J. B. Cloning and characterization of the choline acetyltransferase structural gene (cha-1) from C. elegans. J. Neurosci. 14, 2290–2300 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Alfonso, A., Grundahl, K., Duerr, J. S., Han, H. P. & Rand, J. B. The Caenorhabditis elegans unc-17 gene: a putative vesicular acetylcholine transporter. Science 261, 617–619 (1993).

    Article  CAS  PubMed  Google Scholar 

  47. Nonet, M. L., Grundahl, K., Meyer, B. J. & Rand, J. B. Synaptic function is impaired but not eliminated in C. elegans mutants lacking synaptotagmin. Cell 73, 1291–1305 (1993).

    Article  CAS  PubMed  Google Scholar 

  48. Maruyama, H., Rakow, T. L. & Maruyama, I. N. Synaptic exocytosis and nervous system development impaired in Caenorhabditis elegans unc-13 mutants. Neuroscience 104, 287–297 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Harada, S., Hori, I., Yamamoto, H. & Hosono, R. Mutations in the unc-41 gene cause elevation of acetylcholine levels. J. Neurochem. 63, 439–446 (1994).

    Article  CAS  PubMed  Google Scholar 

  50. Halevi, S. et al. The C. elegans ric-3 gene is required for maturation of nicotinic acetylcholine receptors. EMBO J. 21, 1012–1020 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Campbell, W. C. Benzimidazoles: veterinary uses. Parasitol. Today 6, 130–133 (1990).

    Article  CAS  PubMed  Google Scholar 

  52. Cook, G. C. Use of benzimidazole chemotherapy in human helminthiases: indications and efficacy. Parasitol. Today 6, 133–136 (1990).

    Article  CAS  PubMed  Google Scholar 

  53. Lacey, E. Mode of action of benzimidazoles. Parasitol. Today 6, 112–115 (1990).

    Article  CAS  PubMed  Google Scholar 

  54. Driscoll, M., Dean, E., Reilly, E., Bergholz, E. & Chalfie, M. Genetic and molecular analysis of a Caenorhabditis elegans β-tubulin that conveys benzimidazole sensitivity. J. Cell. Biol. 109, 2993–3003 (1989).

    Article  CAS  PubMed  Google Scholar 

  55. Roos, M. H. et al. Molecular analysis of selection for benzimidazole resistance in the sheep parasite Haemonchus contortus. Mol. Biochem. Parasitol. 43, 77–88 (1990).

    Article  CAS  PubMed  Google Scholar 

  56. Lubega, G. W., Klein, R. D., Geary, T. G. & Prichard, R. K. Haemonchus contortus: the role of two β-tubulin gene subfamilies in the resistance to benzimidazole anthelmintics. Biochem. Pharmacol. 47, 1705–1715 (1994).

    Article  CAS  PubMed  Google Scholar 

  57. Kwa, M. S., Veenstra, J. G. & Roos, M. H. Benzimidazole resistance in Haemonchus contortus is correlated with a conserved mutation at amino acid 200 in β-tubulin isotype 1. Mol. Biochem. Parasitol. 63, 299–303 (1994).

    Article  CAS  PubMed  Google Scholar 

  58. Kwa, M. S., Veenstra, J. G., Van Dijk, M. & Roos, M. H. β-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. J. Mol. Biol. 246, 500–510 (1995). The authors report the successful expression of an anthelmintic drug target from a parasitic nematode ( Haemonchus ) in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  59. Omura, S. & Crump, A. The life and times of ivermectin — a success story. Nature Rev. Microbiol. 2, 984–989 (2004).

    Article  CAS  Google Scholar 

  60. Remme, J. H. Research for control: the onchocerciasis experience. Trop. Med. Int. Health. 9, 243–254 (2004).

    Article  PubMed  Google Scholar 

  61. Fritz, L. C., Wang, C. C. & Gorio, A. Avermectin B1a irreversibly blocks postsynaptic potentials at the lobster neuromuscular junction by reducing muscle membrane resistance. Proc. Natl Acad. Sci. USA 76, 2062–2066 (1979).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Duce, I. R. & Scott, R. H. Actions of dihydroavermectin B1a on insect muscle. Br. J. Pharmacol. 85, 395–401 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Cully, D. F. et al. Cloning of an avermectin-sensitive glutamate-gated chloride channel from Caenorhabditis elegans. Nature 371, 707–711 (1994). The first report of the cloning and functional expression of C. elegans glutamate-gated chloride channel subunits which are targeted by ivermectin.

    Article  CAS  PubMed  Google Scholar 

  64. Vassilatis, D. K. et al. Genetic and biochemical evidence for a novel avermectin-sensitive chloride channel in Caenorhabditis elegans. Isolation and characterization. J. Biol. Chem. 272, 33167–33174 (1997).

    Article  CAS  PubMed  Google Scholar 

  65. Yates, D. M., Portillo, V. & Wolstenholme, A. J. The avermectin receptors of Haemonchus contortus and Caenorhabditis elegans. Int. J. Parasitol. 33, 1183–1193 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Dent, J. A., Davis, M. W. & Avery, L. avr-15 encodes a chloride channel subunit that mediates inhibitory glutamatergic neurotransmission and ivermectin sensitivity in Caenorhabditis elegans. EMBO J. 16, 5867–5879 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Dent, J. A., Smith, M. M., Vassilatis, D. K. & Avery, L. The genetics of ivermectin resistance in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 97, 2674–2679 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Flores, C. M., Rogers, S. W., Pabreza, L. A., Wolfe, B. B. & Kellar, K. J. A subtype of nicotinic cholinergic receptor in rat brain is composed of α4 and β2 subunits and is up-regulated by chronic nicotine treatment. Mol. Pharmacol. 41, 31–37 (1992).

    CAS  PubMed  Google Scholar 

  69. Molinari, E. J. et al. Up-regulation of human α7 nicotinic receptors by chronic treatment with activator and antagonist ligands. Eur. J. Pharmacol. 347, 131–139 (1998).

    Article  CAS  PubMed  Google Scholar 

  70. Waggoner, L. E. et al. Long-term nicotine adaptation in Caenorhabditis elegans involves PKC-dependent changes in nicotinic receptor abundance. J. Neurosci. 20, 8802–8811 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Davies, A. G. et al. A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans. Cell 115, 655–666 (2003).

    Article  CAS  PubMed  Google Scholar 

  72. Wang, Z. W., Saifee, O., Nonet, M. L. & Salkoff, L. SLO-1 potassium channels control quantal content of neurotransmitter release at the C. elegans neuromuscular junction. Neuron 32, 867–881 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Saifee, O., Wei, L. & Nonet, M. L. The Caenorhabditis elegans unc-64 locus encodes a syntaxin that interacts genetically with synaptobrevin. Mol. Biol. Cell 9, 1235–1252 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, Z. W., Saifee, O., Nonet, M. L. & Salkoff, L. A neomorphic syntaxin mutation blocks volatile-anesthetic action in Caenorhabditis elegans. Neuron 96, 867–881 (1999).

    Google Scholar 

  75. Hawasli, A. H., Saifee, O., Liu, C., Nonet, M. L. & Crowder, C. M. Resistance to volatile anesthetics by mutations enhancing excitatory neurotransmitter release in Caenorhabditis elegans. Genetics 168, 831–843 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Lackner, M. R., Nurrish, S. J. & Kaplan, J. M. Facilitation of synaptic transmission by EGL-30 Gqα and EGL-8 PLCβ: DAG binding to UNC-13 is required to stimulate acetylcholine release. Neuron 24, 335–346 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998). The classic paper describing RNA interference in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  78. Timmons, L. & Fire, A. Specific interference by ingested dsRNA. Nature 395, 854 (1998).

    Article  CAS  PubMed  Google Scholar 

  79. Tabara, H., Grishok, A. & Mello, C. C. RNAi in C. elegans: soaking in the genome sequence. Science 282, 430–431 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Kamath, R. S. et al. Systematic functional analysis of the Caenorhabditis elegans genome using RNAi. Nature 421, 231–237 (2003). The first 'genome-wide' RNAi feeding screen in C. elegans.

    Article  CAS  PubMed  Google Scholar 

  81. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003).

    Article  CAS  PubMed  Google Scholar 

  82. Colaiacovo, M. P. et al. A targeted RNAi screen for genes involved in chromosome morphogenesis and nuclear organization in the Caenorhabditis elegans germline. Genetics 162, 113–128 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Lee, S. S. et al. A systematic RNAi screen identifies a critical role for mitochondria in C. elegans longevity. Nature Genet. 33, 40–48 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Poulin, G., Nandakumar, R. & Ahringer, J. Genome-wide RNAi screens in Caenorhabditis elegans: impact on cancer research. Oncogene 23, 8340–8345 (2004).

    Article  CAS  PubMed  Google Scholar 

  85. Buckingham, S. D., Esmaeili, B., Wood, M. & Sattelle, D. B. RNA interference: from model organisms towards therapy for neural and neuromuscular disorders. Hum. Mol. Genet. 13, R275–R288 (2004).

    Article  CAS  PubMed  Google Scholar 

  86. Simmer, F. et al. Loss of the putative RNA-directed RNA polymerase RRF-3 makes C. elegans hypersensitive to RNAi. Curr. Biol. 12, 1317–1319 (2002).

    Article  CAS  PubMed  Google Scholar 

  87. Kennedy, S., Wang, D. & Ruvkun, G. A conserved siRNA-degrading RNase negatively regulates RNA interference in C. elegans. Nature 427, 645–649 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Simmer, F. et al. Genome-wide RNAi of C. elegans using the hypersensitive rrf-3 strain reveals novel gene functions. PLoS Biol. 1, E12 (2003).

    Article  PubMed  PubMed Central  Google Scholar 

  89. Appleford, P. J. et al. Functional redundancy of two nucleoside transporters of the ENT family (CeENT1, CeENT2) required for development of Caenorhabditis elegans. Mol. Membr. Biol. 21, 247–259 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Li, S. et al. A map of the interactome network of the metazoan C. elegans. Science 303, 540–543 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Rual, J. F. et al. Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library. Genome Res. 14, 2162–2168 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gaud, A. et al. Prednisone reduces muscle degeneration in dystrophin-deficient Caenorhabditis elegans. Neuromuscul. Disord. 14, 365–370 (2004). This paper provides validation of a chemical screening approach for human drug discovery using a C. elegans model of muscular dystrophy.

    Article  PubMed  Google Scholar 

  93. Ahn, A. H. & Kunkel, L. M. The structural and functional diversity of dystrophin. Nature Genet. 3, 283–291 (1993).

    Article  CAS  PubMed  Google Scholar 

  94. Gieseler, K., Grisoni, K. & Segalat, L. Genetic suppression of phenotypes arising from mutations in dystrophin-related genes in Caenorhabditis elegans. Curr. Biol. 10, 1092–1097 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Melov, S. et al. Extension of life-span with superoxide dismutase/catalase mimetics. Science 289, 1567–1569 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Rong, Y., Doctrow, S. R., Tocco, G. & Baudry, M. EUK-134, a synthetic superoxide dismutase and catalase mimetic, prevents oxidative stress and attenuates kainate-induced neuropathology. Proc. Natl Acad. Sci. USA 96, 9897–9902 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Jung, C. et al. Synthetic superoxide dismutase/catalase mimetics reduce oxidative stress and prolong survival in a mouse amyotrophic lateral sclerosis model. Neurosci. Lett. 304, 157–160 (2001).

    Article  CAS  PubMed  Google Scholar 

  98. Link, C. D. Expression of human β-amyloid peptide in transgenic Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 92, 9368–9372 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Parkinson, J. et al. A transcriptomic analysis of the phylum Nematoda. Nature Genet. 36, 1259–1267 (2004).

    Article  PubMed  Google Scholar 

  100. Ghedin, E., Wang, S., Foster, J. M. & Slatko, B. E. First sequenced genome of a parasitic nematode. Trends Parasitol. 20, 151–153 (2004).

    Article  CAS  PubMed  Google Scholar 

  101. Reynolds, N. K., Schade, M. A. & Miller, K. Convergent, RIC-8 dependent Gα signaling pathways in the C. elegans synaptic signaling network. Genetics 169, 651–670 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Doi, M. & Iwasaki, K. Regulation of retrograde signaling at neuromuscular junctions by the novel C2 domain protein AEX-1. Neuron 33, 249–259 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Patikoglou, G. A. & Koelle, M. R. An N-terminal region of Caenorhabditis elegans RGS proteins EGL-10 and EAT-16 directs inhibition of Gαo versus Gαq signaling. J. Biol. Chem. 277, 47004–47013 (2002).

    Article  CAS  PubMed  Google Scholar 

  104. Bastiani, C. A., Gharib, S., Simon, M. I. & Sternberg, P. W. Caenorhabditis elegans Gαq regulates egg-laying behavior via a PLCβ-independent and serotonin-dependent signaling pathway and likely functions both in the nervous system and in muscle. Genetics 165, 1805–1822 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Schafer, W. R. & Kenyon, C. J. A calcium-channel homologue required for adaptation to dopamine and serotonin in Caenorhabditis elegans. Nature 375, 73–78 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Koushika, S. P. et al. A post-docking role for active zone protein Rim. Nature Neurosci. 4, 997–1005 (2001).

    Article  CAS  PubMed  Google Scholar 

  107. Grunwald, M. E., Mellem, J. E., Strutz, N., Maricq, A. V. & Kaplan, J. M. Clathrin-mediated endocytosis is required for compensatory regulation of GLR-1 glutamate receptors after activity blockade. Proc. Natl Acad. Sci. USA 101, 3190–3195 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Weimer, R. M. et al. Defects in synaptic vesicle docking in unc-18 mutants. Nature Neurosci. 6, 1023–1030 (2003).

    Article  CAS  PubMed  Google Scholar 

  109. Harris, T. W., Hartwieg, E., Horvitz, H. R. & Jorgensen, E. M. Mutations in synaptojanin disrupt synaptic vesicle recycling. J. Cell. Biol. 150, 589–600 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Berwin, B., Floor, E. & Martin, T. F. CAPS (mammalian UNC-31) protein localizes to membranes involved in dense-core vesicle exocytosis. Neuron 21, 137–145 (1998).

    Article  CAS  PubMed  Google Scholar 

  111. Pujol, N., Bonnerot, C., Ewbank, J. J., Kohara, Y. & Thierry-Mieg, D. The Caenorhabditis elegans unc-32 gene encodes alternative forms of a vacuolar ATPase α subunit. J. Biol. Chem. 276, 11913–11921 (2001).

    Article  CAS  PubMed  Google Scholar 

  112. Schafer, W. R., Sanchez, B. M. & Kenyon, C. J. Genes affecting sensitivity to serotonin in Caenorhabditis elegans. Genetics 143, 1219–1230 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. Loria, P. M., Duke, A., Rand, J. B. & Hobert, O. Two neuronal, nuclear-localized RNA binding proteins involved in synaptic transmission. Curr. Biol. 13, 1317–1323 (2003).

    Article  CAS  PubMed  Google Scholar 

  114. Hall, D. H. & Hedgecock, E. M. Kinesin-related gene unc-104 is required for axonal transport of synaptic vesicles in C. elegans. Cell 65, 837–847 (1991).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank S. Aslam and C. Mee for comments on the manuscript.

Author information

Authors and Affiliations

  1. Department of Human Anatomy and Genetics, MRC Functional Genetics Unit, University of Oxford, South Parks Road, Oxford, OX1 3QX, UK

    Andrew K. Jones, Steven D. Buckingham & David B. Sattelle

Authors
  1. Andrew K. Jones
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Steven D. Buckingham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David B. Sattelle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David B. Sattelle.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

DATABASES

Entrez Gene

avr-14

avr-15

ben-1

dys-1

egl-30

glc-1

lev-1

lev-8

LEV-10

lev-11

mev-1

slo-1

tpa-1

unc-22

unc-29

unc-38

unc-50

unc-63

unc-68

unc-74

UNCL

OMIM

Alzheimer's disease

Becker muscular dystrophy

Duchenne muscular dystrophy

FURTHER INFORMATION

Axys Pharmaceuticals

Cambria Biosciences, LLC

CyberGenome Technologies, LLC

Devgen

Divergence LLC

Exelixis Pharmaceuticals, Inc.

The C. elegans Gene Knockout Consortium

The Nef Lab, Hoffmann-La Roche, Basel

WormBase

Glossary

ANTHELMINTIC

A chemical that controls parasitic worms. An example is levamisole, which controls parasitic nematodes.

ENDECTOCIDE

An antiparasitic drug which controls both internal parasites (such as worms) and external parasites (such as ticks). An example is ivermectin.

CHEMISTRY-TO-GENE SCREEN

Following mutagenesis of C. elegans, mutants are screened for resistance to a particular chemical and the resulting mutations are mapped and identified (useful for identifying hitherto unknown drug targets).

NICOTINIC ACETYLCHOLINE RECEPTORS

(nAChRs). Prototypical members of the cys-loop ligand-gated ion channel superfamily classified by the ability of nicotine to activate them. On binding acetylcholine, the natural neurotransmitter activating these receptors, the ion channel is opened transiently resulting in an influx of ions into the cell.

CYS-LOOP LIGAND-GATED ION CHANNEL SUPERFAMILY

An extended family of ligand-gated ion channels, each molecule composed of five subunits arranged around an ion permeable channel. Each subunit is characterised by an extracellular domain containing the cys-loop – two disulfide bond-forming cysteines separated by 13 amino acid residues. Members include nAChRs and ionotropic receptors for GABA, 5-HT3 and glycine.

ACARICIDE

A chemical that controls mites.

RNA INTERFERENCE

(RNAi). The deployment of double-stranded RNA, which results in specific silencing of the corresponding gene through degradation of endogenous RNA.

COPAS

An automated high throughput system that can sort C. elegans (up to 100,000 worms per hour) based on physical and optical parameters.

TWO-HYBRID ANALYSIS

A large-scale yeast-two hybrid screen to identify protein– protein (or 'interactome') networks.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Jones, A., Buckingham, S. & Sattelle, D. Chemistry-to-gene screens in Caenorhabditis elegans. Nat Rev Drug Discov 4, 321–330 (2005). https://doi.org/10.1038/nrd1692

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd1692

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing