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:

Finding function in novel targets: C. elegans as a model organism

Nature Reviews Drug Discovery volume 5, pages 387–399 (2006)Cite this article

Key Points

  • C. elegans is a model organism that has the potential to bridge the gap between in vitro and in vivo approaches by virtue of being amenable to high-throughput technologies while providing physiologically relevant data derived from a whole-animal setting.

  • Several features of C. elegans make it a powerful tool for the pharmaceutical industry. These include being easy to culture; undergoing rapid reproduction with a short generation time enabling large-scale production of animals; small size, which allows assays of more than a hundred animals in a single well of a 96-well plate; transparency, which enables the use of fluorescent markers to study biological processes in vivo; and cellular complexity — C. elegans is a multicellular organism that has many different organs and tissues.

  • Although in many cases a direct translation of human pathology into C. elegans phenotypes is impossible, C. elegans assays emulate certain aspects of human pathology. These help to elucidate the underlying molecular mechanisms and to deliver new approaches for therapeutic strategies, rather than recapitulating human disease pathology in every detail.

  • The benefit of C. elegans over mice or rats is its amenability to whole-animal high-throughput technologies. C. elegans investigations have already fostered a better understanding of the underlying mechanism for several diseases such as Alzheimer's disease, cancer, diabetes and depression.

  • WormBase, a database of C. elegans genetic and genomic information curated by a consortium of researchers, is an excellent resource for those wishing to use C. elegans as a model organism.

  • The availability of C. elegans RNA interference (RNAi) libraries has made it possible to carry out high-throughput genome-wide RNAi, which has shown success in identifying drug targets for diabetes and obesity.

  • C. elegans genetics can also be used to dissect the in vivo action of a drug, even if it modulates several targets. For example, antidepressant drug action can be studied in a functional serotonergic synapse within the context of a whole organism.

  • Although there are intrinsic limitations associated with C. elegans, such as the absence of some human molecular pathways in the worm, and the inability to model the complete pathophysiology of the disease, if the purpose and potential restrictions of the model are defined, the value of C. elegans in high-throughput, whole-organism screens becomes apparent.

Abstract

Despite its apparent simplicity, the nematode worm Caenorhabditis elegans has developed into an important model for biomedical research, particularly in the functional characterization of novel drug targets that have been identified using genomics technologies. The cellular complexity and the conservation of disease pathways between C. elegans and higher organisms, together with the simplicity and cost-effectiveness of cultivation, make for an effective in vivo model that is amenable to whole-organism high-throughput compound screens and large-scale target validation. This review describes how C. elegans models can be used to advance our understanding of the molecular mechanisms of drug action and disease pathogenesis.

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: The serotonergic synapse of C. elegans.
Figure 2: Drug entry route into C. elegans.
Figure 3: Overview of the RNA interference supported target identification process.
Figure 4: Chemical genetics as a tool for target site identification.

Similar content being viewed by others

References

  1. Brenner, S. The genetics of Caenorhabditis elegans. Genetics 77, 71–94 (1974).

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Riddle, D., Blumenthal, T., Meyer, B. & Priess, J. C. elegans II (Cold Spring Harbor Laboratory, New York, 1997).

    Google Scholar 

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

  4. White, J. in The Nematode Caenorhabditis elegans (ed. Wood, W. B.) 81–122 (Cold Spring Harbor Laboratory, New York, 1988).

    Google Scholar 

  5. Sonnhammer, E. L. & Durbin, R. Analysis of protein domain families in Caenorhabditis elegans. Genomics 46, 200–216 (1997).

    CAS  PubMed  Google Scholar 

  6. Lai, C. H., Chou, C. Y., Ch'ang, L. Y., Liu, C. S. & Lin, W. Identification of novel human genes evolutionarily conserved in Caenorhabditis elegans by comparative proteomics. Genome Res. 10, 703–713 (2000).

    CAS  PubMed Central  PubMed  Google Scholar 

  7. Kuwabara, P. E. & O'Neil, N. The use of functional genomics in C. elegans for studying human development and disease. J. Inherit. Metab Dis. 24, 127–138 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Remm, M., Storm, C. E. & Sonnhammer, E. L. Automatic clustering of orthologs and in-paralogs from pairwise species comparisons. J. Mol. Biol. 314, 1041–1052 (2001).

    CAS  PubMed  Google Scholar 

  10. O'Brien, K. P., Westerlund, I. & Sonnhammer, E. L. OrthoDisease: a database of human disease orthologs. Hum. Mutat. 24, 112–119 (2004).

    CAS  PubMed  Google Scholar 

  11. Schuske, K., Beg, A. A. & Jorgensen, E. M. The GABA nervous system in C. elegans. Trends Neurosci. 27, 407–414 (2004).

    CAS  PubMed  Google Scholar 

  12. McIntire, S. L., Reimer, R. J., Schuske, K., Edwards, R. H. & Jorgensen, E. M. Identification and characterization of the vesicular GABA transporter. Nature 389, 870–876 (1997).

    CAS  PubMed  Google Scholar 

  13. Dumoulin, A. et al. Presence of the vesicular inhibitory amino acid transporter in GABAergic and glycinergic synaptic terminal boutons. J. Cell Sci. 112, 811–823 (1999).

    CAS  PubMed  Google Scholar 

  14. Drews, J. Drug discovery: a historical perspective. Science 287, 1960–1964 (2000).

    CAS  PubMed  Google Scholar 

  15. Hopkins, A. L. & Groom, C. R. The druggable genome. Nature Rev. Drug Discov. 1, 727–730 (2002).

    CAS  Google Scholar 

  16. Fire, A. et al. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature 391, 806–811 (1998).

    CAS  PubMed  Google Scholar 

  17. Fraser, A. G. et al. Functional genomic analysis of C. elegans chromosome 1 by systematic RNA interference. Nature 408, 325–330 (2000).

    CAS  PubMed  Google Scholar 

  18. Gonczy, P. et al. Functional genomic analysis of cell division in C. elegans using RNAi of genes on chromosome 3. Nature 408, 331–336 (2000).

    CAS  PubMed  Google Scholar 

  19. Mello, C. C. & Conte, D. Jr. Revealing the world of RNA interference. Nature 431, 338–342 (2004).

    CAS  PubMed  Google Scholar 

  20. Plaetinck, G., Platteeuw, C., Mortier, K. & Bogaert, T. Characterization of gene function using double stranded RNA inhibition. WO Patent 00/01846 (1999).

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

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  23. Kamath, R. S. & Ahringer, J. Genome-wide RNAi screening in Caenorhabditis elegans. Methods 30, 313–321 (2003).

    CAS  PubMed  Google Scholar 

  24. Winston, W. M., Molodowitch, C. & Hunter, C. P. Systemic RNAi in C. elegans requires the putative transmembrane protein SID-1. Science 295, 2456–2459 (2002).

    CAS  PubMed  Google Scholar 

  25. Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).

    CAS  PubMed  Google Scholar 

  26. Yang, S., Tutton, S., Pierce, E. & Yoon, K. Specific double-stranded RNA interference in undifferentiated mouse embryonic stem cells. Mol. Cell Biol. 21, 7807–7816 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Jackson, A. L. et al. Expression profiling reveals off-target gene regulation by RNAi. Nature Biotechnol. 21, 635–637 (2003).

    CAS  Google Scholar 

  28. Sonnichsen, B. et al. Full-genome RNAi profiling of early embryogenesis in Caenorhabditis elegans. Nature 434, 462–469 (2005).

    CAS  PubMed  Google Scholar 

  29. Kamath, R. S., Martinez-Campos, M., Zipperlen, P., Fraser, A. G. & Ahringer, J. Effectiveness of specific RNA-mediated interference through ingested double-stranded RNA in Caenorhabditis elegans. Genome Biol. 2, (2001).

  30. Keating, C. D. et al. Whole-genome analysis of 60 G protein-coupled receptors in Caenorhabditis elegans by gene knockout with RNAi. Curr. Biol. 13, 1715–1720 (2003).

    CAS  PubMed  Google Scholar 

  31. Shi, Y. & Burn, P. Lipid metabolic enzymes: emerging drug targets for the treatment of obesity. Nature Rev. Drug Discov. 3, 695–710 (2004).

    CAS  Google Scholar 

  32. Filippatos, T. D., Kiortsis, D. N., Liberopoulos, E. N., Mikhailidis, D. P. & Elisaf, M. S. A review of the metabolic effects of sibutramine. Curr. Med. Res. Opin. 21, 457–468 (2005).

    CAS  PubMed  Google Scholar 

  33. Curran, M. P. & Scott, L. J. Orlistat: a review of its use in the management of patients with obesity. Drugs 64, 2845–2864 (2004).

    CAS  PubMed  Google Scholar 

  34. Klass, M. R. Aging in the nematode Caenorhabditis elegans: major biological and environmental factors influencing life span. Mech. Ageing Dev. 6, 413–429 (1977).

    CAS  PubMed  Google Scholar 

  35. Lakowski, B. & Hekimi, S. The genetics of caloric restriction in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 95, 13091–13096 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Ashrafi, K. et al. Genome-wide RNAi analysis of Caenorhabditis elegans fat regulatory genes. Nature 421, 268–272 (2003). Excellent example of how to perform an RNAi screen in C. elegans on a genome-wide scale to identify targets for treatment of obesity and diabetes and subsequent prioritization of targets by parallel screening in several C. elegans metabolic disease models.

    CAS  PubMed  Google Scholar 

  37. Stein, L., Sternberg, P., Durbin, R., Thierry-Mieg, J. & Spieth, J. WormBase: network access to the genome and biology of Caenorhabditis elegans. Nucleic Acids Res. 29, 82–86 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  39. Duchaine, T. F. et al. Functional proteomics reveals the biochemical niche of C. elegans DCR-1 in multiple small-RNA-mediated pathways. Cell 124, 343–354 (2006).

    CAS  PubMed  Google Scholar 

  40. Reboul, J. et al. C. elegans ORFeome version 1.1: experimental verification of the genome annotation and resource for proteome-scale protein expression. Nature Genet. 34, 35–41 (2003).

    PubMed  Google Scholar 

  41. Luan, C. H. et al. High-throughput expression of C. elegans proteins. Genome Res. 14, 2102–2110 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Jorgensen, E. M. & Mango, S. E. The art and design of genetic screens: Caenorhabditis elegans. Nature Rev. Genet. 3, 356–369 (2002).

    CAS  PubMed  Google Scholar 

  44. Jones, A. K., Buckingham, S. D. & Sattelle, D. B. Chemistry-to-gene screens in Caenorhabditis elegans. Nature Rev. Drug Discov. 4, 321–330 (2005).

    CAS  Google Scholar 

  45. Zheng, X. F. & Chan, T. F. Chemical genomics: a systematic approach in biological research and drug discovery. Curr. Issues Mol. Biol. 4, 33–43 (2002).

    CAS  PubMed  Google Scholar 

  46. Alaoui-Ismaili, M. H., Lomedico, P. T. & Jindal, S. Chemical genomics: discovery of disease genes and drugs. Drug Discov. Today 7, 292–294 (2002).

    PubMed  Google Scholar 

  47. Ranganathan, R., Sawin, E. R., Trent, C. & Horvitz, H. R. Mutations in the Caenorhabditis elegans serotonin reuptake transporter MOD-5 reveal serotonin-dependent and -independent activities of fluoxetine. J. Neurosci. 21, 5871–5884 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Kaletta, T., Butler, L. & Bogaert, T. in Model Organisms in Drug Discovery (eds Carroll, P. M. & Fitzgerald, K.) 41–79 (John Wiley & Sons, 2003).

    Google Scholar 

  49. Lackner, M. R. et al. Chemical genetics identifies Rab geranylgeranyl transferase as an apoptotic target of farnesyl transferase inhibitors. Cancer Cell 7, 325–336 (2005). The authors describe how to build and validate a C. elegans assay for the investigation of multiple in vivo modes of action of farnesyl transferase inhibitors (FTIs), to identify and prioritize targets of FTIs and to validate these novel targets in mammalian systems.

    CAS  PubMed  Google Scholar 

  50. Karp, J. E. et al. Current status of clinical trials of farnesyltransferase inhibitors. Curr. Opin. Oncol. 13, 470–476 (2001).

    CAS  PubMed  Google Scholar 

  51. O'Regan, R. M. & Khuri, F. R. Farnesyl transferase inhibitors: the next targeted therapies for breast cancer? Endocr. Relat. Cancer 11, 191–205 (2004).

    CAS  PubMed  Google Scholar 

  52. Hara, M. & Han, M. Ras farnesyltransferase inhibitors suppress the phenotype resulting from an activated ras mutation in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 92, 3333–3337 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Dempsey, C. M., Mackenzie, S. M., Gargus, A., Blanco, G. & Sze, J. Y. Serotonin (5HT), fluoxetine, imipramine and dopamine target distinct 5HT receptor signaling to modulate Caenorhabditis elegans egg-laying behavior. Genetics 169, 1425–1436 (2005). Good example of the conservation of human and C. elegans pharmacology at the cellular level.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Delmas, P. Polycystins: from mechanosensation to gene regulation. Cell 118, 145–148 (2004).

    CAS  PubMed  Google Scholar 

  55. Barr, M. M. & Sternberg, P. W. A polycystic kidney-disease gene homologue required for male mating behaviour in C. elegans. Nature 401, 386–389 (1999).

    CAS  PubMed  Google Scholar 

  56. Barr, M. M. et al. The Caenorhabditis elegans autosomal dominant polycystic kidney disease gene homologs lov-1 and pkd-2 act in the same pathway. Curr. Biol. 11, 1341–1346 (2001).

    CAS  PubMed  Google Scholar 

  57. Kaletta, T. et al. Towards understanding the polycystins. Nephron Exp. Nephrol. 93, e9–e17 (2003).

    CAS  PubMed  Google Scholar 

  58. Nauli, S. M. et al. Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nature Genet. 33, 129–137 (2003).

    CAS  PubMed  Google Scholar 

  59. Lipton, J. Mating worms and the cystic kidney: Caenorhabditis elegans as a model for renal disease. Pediatr. Nephrol. 20, 1531–1536 (2005).

    PubMed  Google Scholar 

  60. Parker, J. A., Holbert, S., Lambert, E., Abderrahmane, S. & Neri, C. Genetic and pharmacological suppression of polyglutamine-dependent neuronal dysfunction in Caenorhabditis elegans. J. Mol. Neurosci. 23, 61–68 (2004).

    CAS  PubMed  Google Scholar 

  61. Sifri, C. D., Begun, J. & Ausubel, F. M. The worm has turned — microbial virulence modeled in Caenorhabditis elegans. Trends Microbiol. 13, 119–127 (2005).

    CAS  PubMed  Google Scholar 

  62. Kurz, C. L. & Ewbank, J. J. Caenorhabditis elegans: an emerging genetic model for the study of innate immunity. Nature Rev. Genet. 4, 380–390 (2003).

    CAS  PubMed  Google Scholar 

  63. Tenor, J. L., McCormick, B. A., Ausubel, F. M. & Aballay, A. Caenorhabditis elegans-based screen identifies Salmonella virulence factors required for conserved host–pathogen interactions. Curr. Biol. 14, 1018–1024 (2004).

    CAS  PubMed  Google Scholar 

  64. Sundaram, M. & Greenwald, I. Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans. Genetics 135, 765–783 (1993).

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Levitan, D. & Greenwald, I. Facilitation of lin-12-mediated signalling by sel-12, a Caenorhabditis elegans S182 Alzheimer's disease gene. Nature 377, 351–354 (1995).

    CAS  PubMed  Google Scholar 

  66. Sherrington, R. et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease. Nature 375, 754–760 (1995).

    CAS  PubMed  Google Scholar 

  67. Wittenburg, N. et al. Presenilin is required for proper morphology and function of neurons in C. elegans. Nature 406, 306–309 (2000).

    CAS  PubMed  Google Scholar 

  68. Levitan, D. et al. Assessment of normal and mutant human presenilin function in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 93, 14940–14944 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  69. De Strooper, B. et al. A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain. Nature 398, 518–522 (1999).

    CAS  PubMed  Google Scholar 

  70. Ogg, S. et al. The Fork head transcription factor DAF-16 transduces insulin-like metabolic and longevity signals in C. elegans. Nature 389, 994–999 (1997).

    CAS  PubMed  Google Scholar 

  71. Nakae, J. et al. Regulation of insulin action and pancreatic β-cell function by mutated alleles of the gene encoding forkhead transcription factor Foxo1. Nature Genet. 32, 245–253 (2002).

    CAS  PubMed  Google Scholar 

  72. Hujova, J. et al. Characterization of gana-1, a Caenorhabditis elegans gene encoding a single ortholog of vertebrate α-galactosidase and α-N-acetylgalactosaminidase. BMC Cell Biol. 6, 5 (2005). An interesting example of orthology clusters with between one and many relationships.

    PubMed Central  PubMed  Google Scholar 

  73. Jagasia, R., Grote, P., Westermann, B. & Conradt, B. DRP-1-mediated mitochondrial fragmentation during EGL-1-induced cell death in C. elegans. Nature 433, 754–760 (2005).

    CAS  PubMed  Google Scholar 

  74. Hengartner, M. O. & Horvitz, H. R. Activation of C. elegans cell death protein CED-9 by an amino-acid substitution in a domain conserved in Bcl-2. Nature 369, 318–320 (1994).

    CAS  PubMed  Google Scholar 

  75. 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 Central  PubMed  Google Scholar 

  76. Wicks, S. R., Yeh, R. T., Gish, W. R., Waterston, R. H. & Plasterk, R. H. Rapid gene mapping in Caenorhabditis elegans using a high density polymorphism map. Nature Genet. 28, 160–164 (2001).

    CAS  PubMed  Google Scholar 

  77. Swan, K. A. et al. High-throughput gene mapping in Caenorhabditis elegans. Genome Res. 12, 1100–1105 (2002).

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Zipperlen, P. et al. A universal method for automated gene mapping. Genome Biol. 6, R19 (2005).

    PubMed Central  PubMed  Google Scholar 

  79. Gurney, M. E., Geary, T., Ellerbrbrock, B. R. & Thomas, E. M. A nematode drug screen for modulators of mammalian disorders. WO Patent 00/73493 (2000).

  80. Ellerbrock, B. R., Coscarelli, E. M., Gurney, M. E. & Geary, T. G. Screening for presenilin inhibitors using the free-living nematode, Caenorhabditis elegans. J. Biomol. Screen. 9, 147–152 (2004).

    CAS  PubMed  Google Scholar 

  81. Desai, C., Garriga, G., McIntire, S. L. & Horvitz, H. R. A genetic pathway for the development of the Caenorhabditis elegans HSN motor neurons. Nature 336, 638–646 (1988).

    CAS  PubMed  Google Scholar 

  82. Desai, C. & Horvitz, H. R. Caenorhabditis elegans mutants defective in the functioning of the motor neurons responsible for egg laying. Genetics 121, 703–721 (1989).

    CAS  PubMed Central  PubMed  Google Scholar 

  83. Weinshenker, D., Garriga, G. & Thomas, J. H. Genetic and pharmacological analysis of neurotransmitters controlling egg laying in C. elegans. J. Neurosci. 15, 6975–6985 (1995).

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Kim, J. et al. Genes affecting the activity of nicotinic receptors involved in Caenorhabditis elegans egg-laying behavior. Genetics 157, 1599–1610 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Sze, J. Y., Victor, M., Loer, C., Shi, Y. & Ruvkun, G. Food and metabolic signalling defects in a Caenorhabditis elegans serotonin-synthesis mutant. Nature 403, 560–564 (2000).

    CAS  PubMed  Google Scholar 

  86. Loer, C. M. & Kenyon, C. J. Serotonin-deficient mutants and male mating behavior in the nematode Caenorhabditis elegans. J. Neurosci. 13, 5407–5417 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  87. Weimer, R. M. & Jorgensen, E. M. Controversies in synaptic vesicle exocytosis. J. Cell Sci. 116, 3661–3666 (2003).

    CAS  PubMed  Google Scholar 

  88. Hosono, R. & Kamiya, Y. Additional genes which result in an elevation of acetylcholine levels by mutations in Caenorhabditis elegans. Neurosci. Lett. 128, 243–244 (1991).

    CAS  PubMed  Google Scholar 

  89. Hosono, R. et al. The unc-18 gene encodes a novel protein affecting the kinetics of acetylcholine metabolism in the nematode Caenorhabditis elegans. J. Neurochem. 58, 1517–1525 (1992).

    CAS  PubMed  Google Scholar 

  90. White, J. G., Southgate, E., Thomas, J. N. & Brenner, S. The structure of the nervous system of the nematode Caenorhabditis elegans. Phil. Trans. R. Soc. London B 314, 1–340 (1986).

    CAS  Google Scholar 

  91. Lee, Y. S. et al. Characterization of GAR-2, a novel G protein-linked acetylcholine receptor from Caenorhabditis elegans. J. Neurochem. 75, 1800–1809 (2000).

    CAS  PubMed  Google Scholar 

  92. van der Linden, A. M., Simmer, F., Cuppen, E. & Plasterk, R. H. The G-protein β-subunit GPB-2 in Caenorhabditis elegans regulates the Goα–Gqα signaling network through interactions with the regulator of G-protein signaling proteins EGL-10 and EAT-16. Genetics 158, 221–235 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Perkins, L. A., Hedgecock, E. M., Thomson, J. N. & Culotti, J. G. Mutant sensory cilia in the nematode Caenorhabditis elegans. Dev. Biol. 117, 456–487 (1986).

    CAS  PubMed  Google Scholar 

  94. Smith, H. & Campbell, W. C. Effect of ivermectin on Caenorhabditis elegans larvae previously exposed to alcoholic immobilization. J. Parasitol. 82, 187–188 (1996).

    CAS  PubMed  Google Scholar 

  95. Choy, R. K., Kemner, J. M. & Thomas, J. H. Fluoxetine-resistance genes in Caenorhabditis elegans function in the intestine and may act in drug transport. Genetics 172, 885–892 (2006).

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Pierce, S. B. et al. Regulation of DAF-2 receptor signaling by human insulin and ins-1, a member of the unusually large and diverse C. elegans insulin gene family. Genes Dev. 15, 672–686 (2001).

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Feichtinger, R. & Bogaert, T. Compound screens relating to insulin deficiency or insulin resistance. WO Patent 01/93669 (2001).

  98. Harrington, L. A. & Harley, C. B. Effect of vitamin E on lifespan and reproduction in Caenorhabditis elegans. Mech. Ageing Dev. 43, 71–78 (1988).

    CAS  PubMed  Google Scholar 

  99. Kimura, K. D., Tissenbaum, H. A., Liu, Y. & Ruvkun, G. daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans. Science 277, 942–946 (1997).

    CAS  PubMed  Google Scholar 

  100. Tissenbaum, H. A. & Guarente, L. Model organisms as a guide to mammalian aging. Dev. Cell 2, 9–19 (2002).

    CAS  PubMed  Google Scholar 

  101. Houthoofd, K. et al. DAF-2 pathway mutations and food restriction in aging Caenorhabditis elegans differentially affect metabolism. Neurobiol. Aging 26, 689–696 (2005).

    CAS  PubMed  Google Scholar 

  102. Holzenberger, M. et al. IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421, 182–187 (2003).

    CAS  PubMed  Google Scholar 

  103. Baba, T. et al. Estrogen, insulin, and dietary signals cooperatively regulate longevity signals to enhance resistance to oxidative stress in mice. J. Biol. Chem. 280, 16417–16426 (2005).

    CAS  PubMed  Google Scholar 

  104. Sternberg, P. W. & Han, M. Genetics of RAS signaling in C. elegans. Trends Genet. 14, 466–472 (1998).

    CAS  PubMed  Google Scholar 

  105. Fisher, J., Piterman, N., Hubbard, E. J., Stern, M. J. & Harel, D. Computational insights into Caenorhabditis elegans vulval development. Proc. Natl Acad. Sci. USA 102, 1951–1956 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  106. Bergamaschi, D. et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nature Genet. 33, 162–167 (2003).

    CAS  PubMed  Google Scholar 

  107. Deng, X. et al. Caenorhabditis elegans ABL-1 antagonizes p53-mediated germline apoptosis after ionizing irradiation. Nature Genet. 36, 906–912 (2004).

    CAS  PubMed  Google Scholar 

  108. Boulton, S. J. et al. BRCA1/BARD1 orthologs required for DNA repair in Caenorhabditis elegans. Curr. Biol. 14, 33–39 (2004).

    CAS  PubMed  Google Scholar 

  109. Link, C. D. Transgenic invertebrate models of age-associated neurodegenerative diseases. Mech. Ageing Dev. 122, 1639–1649 (2001).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Westlund, B., Stilwell, G. & Sluder, A. Invertebrate disease models in neurotherapeutic discovery. Curr. Opin. Drug Discov. Devel. 7, 169–178 (2004).

    CAS  PubMed  Google Scholar 

  112. Link, C. D. Transgenic invertebrate models of age-associated neurodegenerative diseases. Mech. Ageing Dev. 122, 1639–1649 (2001).

    CAS  PubMed  Google Scholar 

  113. Lakso, M. et al. Dopaminergic neuronal loss and motor deficits in Caenorhabditis elegans overexpressing human α-synuclein. J. Neurochem. 86, 165–172 (2003).

    CAS  PubMed  Google Scholar 

  114. Nass, R., Hall, D. H., Miller, D. M., III & Blakely, R. D. Neurotoxin-induced degeneration of dopamine neurons in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 99, 3264–3269 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  115. Faber, P. W., Alter, J. R., MacDonald, M. E. & Hart, A. C. Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron. Proc. Natl Acad. Sci. USA 96, 179–184 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  116. Nollen, E. A. et al. Genome-wide RNA interference screen identifies previously undescribed regulators of polyglutamine aggregation. Proc. Natl Acad. Sci. USA 101, 6403–6408 (2004).

    CAS  PubMed Central  PubMed  Google Scholar 

  117. 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).

    CAS  PubMed  Google Scholar 

  118. Yanik, M. F. et al. Neurosurgery: functional regeneration after laser axotomy. Nature 432, 822 (2004).

    CAS  PubMed  Google Scholar 

  119. Gaud, A. et al. Prednisone reduces muscle degeneration in dystrophin-deficient Caenorhabditis elegans. Neuromuscul. Disord. 14, 365–370 (2004).

    PubMed  Google Scholar 

  120. Kim, H., Rogers, M. J., Richmond, J. E. & McIntire, S. L. SNF-6 is an acetylcholine transporter interacting with the dystrophin complex in Caenorhabditis elegans. Nature 430, 891–896 (2004).

    CAS  PubMed  Google Scholar 

  121. Griffitts, J. S. et al. Glycolipids as receptors for Bacillus thuringiensis crystal toxin. Science 307, 922–925 (2005).

    CAS  PubMed  Google Scholar 

  122. Kurz, C. L. et al. Virulence factors of the human opportunistic pathogen Serratia marcescens identified by in vivo screening. EMBO J. 22, 1451–1460 (2003).

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Devgen, Technologie-park 30, Gent, B-9052, Belgium

    Titus Kaletta

  2. Institute of Molecular Biology, University of Zurich, Winterhurerstrasse 190, Zurich, 8057, Switzerland

    Michael O. Hengartner

Authors
  1. Titus Kaletta
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Michael O. Hengartner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Titus Kaletta.

Ethics declarations

Competing interests

T.K. is employed by Devgen NV. M.H. is a co-founder of Devgen NV. Both authors have shares in Devgen NV.

Related links

Related links

DATABASES

OMIM

Alzheimer's disease

Huntington's disease

Parkinson's disease

FURTHER INFORMATION

InParanoid

OrthoDisease

Glossary

Chemical genetics

The investigation of the effect of a small molecule on an organism when a certain gene activity is increased or decreased; contrasts with chemical genomics studies, which look at the effect of a small-molecule compound on gene expression.

Cognate target

The protein to which a compound binds to mediate its physiological effect.

Porsolt forced-swim test

Rats that are forced to swim in a cylinder from which they cannot escape will, after an initial period of vigorous activity, adopt a characteristic immobile posture that can be readily identified. Antidepressants will delay onset of immobility.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Kaletta, T., Hengartner, M. Finding function in novel targets: C. elegans as a model organism. Nat Rev Drug Discov 5, 387–399 (2006). https://doi.org/10.1038/nrd2031

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrd2031

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