Immediate activation of chemosensory neuron gene expression by bacterial metabolites is selectively induced by distinct cyclic GMP-dependent pathways in Caenorhabditis elegans

Autoři: Jaeseok Park aff001;  Joshua D. Meisel aff002;  Dennis H. Kim aff001
Působiště autorů: Division of Infectious Diseases, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, United States of America aff001;  Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America aff002
Vyšlo v časopise: Immediate activation of chemosensory neuron gene expression by bacterial metabolites is selectively induced by distinct cyclic GMP-dependent pathways in Caenorhabditis elegans. PLoS Genet 16(8): e1008505. doi:10.1371/journal.pgen.1008505
Kategorie: Research Article
doi: 10.1371/journal.pgen.1008505


Dynamic gene expression in neurons shapes fundamental processes in the nervous systems of animals. However, how neuronal activation by different stimuli can lead to distinct transcriptional responses is not well understood. We have been studying how microbial metabolites modulate gene expression in chemosensory neurons of Caenorhabditis elegans. Considering the diverse environmental stimuli that can activate chemosensory neurons of C. elegans, we sought to understand how specific transcriptional responses can be generated in these neurons in response to distinct cues. We have focused on the mechanism of rapid (<6 min) and selective transcriptional induction of daf-7, a gene encoding a TGF-β ligand, in the ASJ chemosensory neurons in response to the pathogenic bacterium Pseudomonas aeruginosa. DAF-7 is required for the protective behavioral avoidance of P. aeruginosa by C. elegans. Here, we define the involvement of two distinct cyclic GMP (cGMP)-dependent pathways that are required for daf-7 expression in the ASJ neuron pair in response to P. aeruginosa. We show that a calcium-independent pathway dependent on the cGMP-dependent protein kinase G (PKG) EGL-4, and a canonical calcium-dependent signaling pathway dependent on the activity of a cyclic nucleotide-gated channel subunit CNG-2, function in parallel to activate rapid, selective transcription of daf-7 in response to P. aeruginosa metabolites. Our data suggest that fast, selective early transcription of neuronal genes require PKG in shaping responses to distinct microbial stimuli in a pair of C. elegans chemosensory neurons.

Klíčová slova:

Caenorhabditis elegans – cGMP signaling – DNA transcription – Gene expression – Metabolic pathways – Neurons – Pseudomonas aeruginosa – Signal transduction


1. Hildebrand JG, Shepherd GM. Mechanisms of olfactory discrimination: converging evidence for common principles across phyla. Annu Rev Neurosci. 1997;20: 595–631. doi: 10.1146/annurev.neuro.20.1.595 9056726

2. Yarmolinsky DA, Zuker CS, Ryba NJP. Common sense about taste: from mammals to insects. Cell. 2009;139: 234–244. doi: 10.1016/j.cell.2009.10.001 19837029

3. Yohe LR, Brand P. Evolutionary ecology of chemosensation and its role in sensory drive. Curr Zool. 2018;64: 525–533. doi: 10.1093/cz/zoy048 30108633

4. Flavell SW, Greenberg ME. Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system. Annu Rev Neurosci. 2008;31: 563–590. doi: 10.1146/annurev.neuro.31.060407.125631 18558867

5. Hilbert ZA, Kim DH. Sexually dimorphic control of gene expression in sensory neurons regulates decision-making behavior in C. elegans. Elife. 2017;6. doi: 10.7554/eLife.21166 28117661

6. Meisel JD, Panda O, Mahanti P, Schroeder FC, Kim DH. Chemosensation of bacterial secondary metabolites modulates neuroendocrine signaling and behavior of C. elegans. Cell. 2014;159: 267–80. doi: 10.1016/j.cell.2014.09.011 25303524

7. Kim DH, Flavell SW. Host-Microbe Interactions and the Behavior of C. elegans. Journal of Neurogenetics. 2020.

8. Curtis V, Biran A. Dirt, disgust, and disease. Is hygiene in our genes? Perspect Biol Med. 2001;44: 17–31. doi: 10.1353/pbm.2001.0001 11253302

9. Chiu IM, Heesters BA, Ghasemlou N, Von Hehn CA, Zhao F, Tran J, et al. Bacteria activate sensory neurons that modulate pain and inflammation. Nature. 2013;501: 52–57. doi: 10.1038/nature12479 23965627

10. Gerbe F, Sidot E, Smyth DJ, Ohmoto M, Matsumoto I, Dardalhon V, et al. Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites. Nature. 2016;529: 226–230. doi: 10.1038/nature16527 26762460

11. Howitt MR, Lavoie S, Michaud M, Blum AM, Tran SV, Weinstock JV, et al. Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut. Science. 2016;351: 1329–1333. doi: 10.1126/science.aaf1648 26847546

12. von Moltke J, Ji M, Liang H-E, Locksley RM. Tuft-cell-derived IL-25 regulates an intestinal ILC2-epithelial response circuit. Nature. 2016;529: 221–225. doi: 10.1038/nature16161 26675736

13. Schulenburg H, Félix M-A. The Natural Biotic Environment of Caenorhabditis elegans. Genetics. 2017;206: 55–86. doi: 10.1534/genetics.116.195511 28476862

14. Bargmann C. Chemosensation in C. elegans. Wormbook. 2006; 1–29. doi: 10.1895/wormbook.1.123.1 18050433

15. Tan MW, Mahajan-Miklos S, Ausubel FM. Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis. Proc Natl Acad Sci USA. 1999;96: 715–720. doi: 10.1073/pnas.96.2.715 9892699

16. Zhang Y, Lu H, Bargmann CI. Pathogenic bacteria induce aversive olfactory learning in Caenorhabditis elegans. Nature. 2005;438: 179–84. doi: 10.1038/nature04216 16281027

17. Meisel J, Kim D. Behavioral avoidance of pathogenic bacteria by Caenorhabditis elegans. Trends in Immunology. 2014;35: 465470. doi: 10.1016/ 25240986

18. Ohta A, Ujisawa T, Sonoda S, Kuhara A. Light and pheromone-sensing neurons regulates cold habituation through insulin signalling in Caenorhabditis elegans. Nature Communications. 2014;5: 4412. doi: 10.1038/ncomms5412 25048458

19. Wang W, Qin L-W, Wu T-H, Ge C-L, Wu Y-Q, Zhang Q, et al. cGMP Signalling Mediates Water Sensation (Hydrosensation) and Hydrotaxis in Caenorhabditis elegans. Scientific Reports. 2016;6: 19779. doi: 10.1038/srep19779 26891989

20. Zaslaver A, Liani I, Shtangel O, Ginzburg S, Yee L, Sternberg PW. Hierarchical sparse coding in the sensory system of Caenorhabditis elegans. Proc Natl Acad Sci. 2015;112: 1185–1189. doi: 10.1073/pnas.1423656112 25583501

21. Wojtyniak M, Brear AG, Damien M O, Sengupta P. Cell- and subunit-specific mechanisms of CNG channel ciliary trafficking and localization in C. elegans. J Cell Sci. 2013;126: 4381–95. doi: 10.1242/jcs.127274 23886944

22. Liu J, Ward A, Gao J, Dong Y, Nishio N, Inada H, et al. C. elegans phototransduction requires a G protein-dependent cGMP pathway and a taste receptor homolog. Nat Neurosci. 2010;13: 715–722. doi: 10.1038/nn.2540 20436480

23. Cho CE, Brueggemann C, L’Etoile ND, Bargmann CI. Parallel encoding of sensory history and behavioral preference during Caenorhabditis elegans olfactory learning. Elife. 2016;5. doi: 10.7554/eLife.14000 27383131

24. Juang B-T, Gu C, Starnes L, Palladino F, Goga A, Kennedy S, et al. Endogenous nuclear RNAi mediates behavioral adaptation to odor. Cell. 2013;154: 1010–1022. doi: 10.1016/j.cell.2013.08.006 23993094

25. Krzyzanowski MC, Brueggemann C, Ezak MJ, Wood JF, Michaels KL, Jackson CA, et al. The C. elegans cGMP-dependent protein kinase EGL-4 regulates nociceptive behavioral sensitivity. PLoS Genet. 2013;9: e1003619. doi: 10.1371/journal.pgen.1003619 23874221

26. Lee JI, Damien M O, Jeffery E-A, Juang B-T, Kaye JA, Hamilton SO, et al. Nuclear entry of a cGMP-dependent kinase converts transient into long-lasting olfactory adaptation. Proc National Acad Sci. 2010;107: 6016–6021. doi: 10.1073/pnas.1000866107 20220099

27. L’Etoile ND, Coburn CM, Eastham J, Kistler A, Gallegos G, Bargmann CI. The Cyclic GMP-Dependent Protein Kinase EGL-4 Regulates Olfactory Adaptation in C. elegans. Neuron. 2002;36: 1079–89. doi: 10.1016/s0896-6273(02)01066-8 12495623

28. O’Halloran DM, Hamilton OS, Lee JI, Gallegos M, L’Etoile ND. Changes in cGMP levels affect the localization of EGL-4 in AWC in Caenorhabditis elegans. PLoS ONE. 2012;7: e31614. doi: 10.1371/journal.pone.0031614 22319638

29. O’Halloran DM, Altshuler-Keylin S, Lee JI, L’Etoile ND. Regulators of AWC-mediated olfactory plasticity in Caenorhabditis elegans. PLoS Genet. 2009;5: e1000761. doi: 10.1371/journal.pgen.1000761 20011101

30. Raizen DM, Zimmerman JE, Maycock MH, Ta UD, You Y, Sundaram MV, et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature. 2008;451: nature06535. doi: 10.1038/nature06535 18185515

31. Trent C, Tsuing N, Horvitz HR. Egg-laying defective mutants of the nematode Caenorhabditis elegans. Genetics. 1983;104: 619–647. 11813735

32. van der Linden AM, Wiener S, You YJ, Kim K, Avery L, Sengupta P. The EGL-4 PKG acts with KIN-29 salt-inducible kinase and protein kinase A to regulate chemoreceptor gene expression and sensory behaviors in Caenorhabditis elegans. Genetics. 2008;180: 1475–91. doi: 10.1534/genetics.108.094771 18832350

33. You Y, Kim J, Raizen DM, Avery L. Insulin, cGMP, and TGF-beta signals regulate food intake and quiescence in C. elegans: a model for satiety. Cell Metab. 2008;7: 249–257. doi: 10.1016/j.cmet.2008.01.005 18316030

34. Gudi T, Lohmann S, Pilz R. Regulation of gene expression by cyclic GMP-dependent protein kinase requires nuclear translocation of the kinase: identification of a nuclear localization signal. Mol Cell Biol. 1997;17: 5244–5254. doi: 10.1128/mcb.17.9.5244 9271402

35. Podda MV, Grassi C. New perspectives in cyclic nucleotide-mediated functions in the CNS: the emerging role of cyclic nucleotide-gated (CNG) channels. Pflugers Arch. 2014;466: 1241–1257. doi: 10.1007/s00424-013-1373-2 24142069

36. Belsham DD, Wetsel WC, Mellon PL. NMDA and nitric oxide act through the cGMP signal transduction pathway to repress hypothalamic gonadotropin-releasing hormone gene expression. EMBO J. 1996;15: 538–547. 8599937

37. Chen Y, Zhuang S, Cassenaer S, Casteel DE, Gudi T, Boss GR, et al. Synergism between calcium and cyclic GMP in cyclic AMP response element-dependent transcriptional regulation requires cooperation between CREB and C/EBP-beta. Mol Cell Biol. 2003;23: 4066–4082. doi: 10.1128/mcb.23.12.4066-4082.2003 12773552

38. Lee SA, Park JK, Kang EK, Bae HR, Bae KW, Park HT. Calmodulin-dependent activation of p38 and p42/44 mitogen-activated protein kinases contributes to c-fos expression by calcium in PC12 cells: modulation by nitric oxide. Brain Res Mol Brain Res. 2000;75: 16–24. doi: 10.1016/s0169-328x(99)00280-6 10648884

39. Peunova N, Enikolopov G. Amplification of calcium-induced gene transcription by nitric oxide in neuronal cells. Nature. 1993;364: 450–453. doi: 10.1038/364450a0 8392663

40. Brenner S. The genetics of Caenorhabditis elegans. Genetics. 1974;77: 71–94. 4366476

41. Fierro-González JC, Cornils A, Alcedo J, Miranda-Vizuete A, Swoboda P. The thioredoxin TRX-1 modulates the function of the insulin-like neuropeptide DAF-28 during dauer formation in Caenorhabditis elegans. PLoS ONE. 2011;6: e16561. doi: 10.1371/journal.pone.0016561 21304598

42. Chronis N, Zimmer M, Bargmann CI. Microfluidics for in vivo imaging of neuronal and behavioral activity in Caenorhabditis elegans. Nat Methods. 2007;4: 727–31. doi: 10.1038/nmeth1075 17704783

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