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NeuroMolecular Medicine

, Volume 20, Issue 4, pp 419–436 | Cite as

The Toll Pathway in the Central Nervous System of Flies and Mammals

  • Anat Shmueli
  • Tali Shalit
  • Eitan OkunEmail author
  • Galit Shohat-OphirEmail author
Review Paper

Abstract

Toll receptors, first identified to regulate embryogenesis and immune responses in the adult fly and subsequently defined as the principal sensors of infection in mammals, are increasingly appreciated for their impact on the homeostasis of the central as well as the peripheral nervous systems. Whereas in the context of immunity, the fly Toll and the mammalian TLR pathways have been researched in parallel, the expression pattern and functionality have largely been researched disparately. Herein, we provide data on the expression pattern of the Toll homologues, signaling components, and downstream effectors in ten different cell populations of the adult fly central nervous system (CNS). We have compared the expression of the different Toll pathways in the fly to the expression of TLRs in the mouse brain and discussed the implications with respect to commonalities, differences, and future perspectives.

Keywords

Toll Drosophila CNS Innate immunity TLR 

Notes

Acknowledgements

This work was conducted at the Paul Feder laboratory for Alzheimer’s disease research and by the Israel Science Foundation (384/14).

Compliance with Ethical Standards

Conflict of interest

The authors declare no conflict of interests.

Ethical Approval

All experimental procedures described in this manuscript were conducted in accordance to the Institutional Animal Care and Use Committee at Bar Ilan University.

Supplementary material

12017_2018_8515_MOESM1_ESM.pdf (4.4 mb)
Supplementary material 1 (PDF 4517 KB)
12017_2018_8515_MOESM2_ESM.docx (77 kb)
Supplementary material 2 (DOCX 77 KB)

References

  1. Akhouayri, I., Turc, C., Royet, J., & Charroux, B. (2011). Toll-8/Tollo negatively regulates antimicrobial response in the Drosophila respiratory epithelium. PLoS Pathogens, 7, e1002319.PubMedPubMedCentralGoogle Scholar
  2. Anders, S., Pyl, P. T., & Huber, W. (2015). HTSeq—a Python framework to work with high-throughput sequencing data. Bioinformatics, 31, 166–169.PubMedGoogle Scholar
  3. Andrade, W. A., Souza Mdo, C., Ramos-Martinez, E., Nagpal, K., Dutra, M. S., Melo, M. B., Bartholomeu, D. C., Ghosh, S., Golenbock, D. T., & Gazzinelli, R. T. (2013). Combined action of nucleic acid-sensing Toll-like receptors and TLR11/TLR12 heterodimers imparts resistance to Toxoplasma gondii in mice. Cell Host & Microbe, 13, 42–53.Google Scholar
  4. Ayyar, S., Pistillo, D., Calleja, M., Brookfield, A., Gittins, K., Goldstone, C., & Simpson, P. (2007). NF-kappaB/Rel-mediated regulation of the neural fate in Drosophila. PLoS ONE, 2, e1178.PubMedPubMedCentralGoogle Scholar
  5. Ballard, S. L., Miller, D. L., & Ganetzky, B. (2014). Retrograde neurotrophin signaling through Tollo regulates synaptic growth in Drosophila. J Cell Biol, 204, 1157–1172.PubMedPubMedCentralGoogle Scholar
  6. Bischoff, V., Vignal, C., Boneca, I. G., Michel, T., Hoffmann, J. A., & Royet, J. (2004). Function of the drosophila pattern-recognition receptor PGRP-SD in the detection of Gram-positive bacteria. Nature Immunology, 5, 1175–1180.PubMedGoogle Scholar
  7. Brennan, C. A., & Anderson, K. V. (2004). Drosophila: the genetics of innate immune recognition and response. Annual Review of Immunology, 22, 457–483.PubMedGoogle Scholar
  8. Broz, P., & Monack, D. M. (2013). Newly described pattern recognition receptors team up against intracellular pathogens. Annual Review of Immunology, 13, 551–565.Google Scholar
  9. Buchon, N., Poidevin, M., Kwon, H. M., Guillou, A., Sottas, V., Lee, B. L., & Lemaitre, B. (2009). A single modular serine protease integrates signals from pattern-recognition receptors upstream of the Drosophila Toll pathway. Proceedings of the National Academy of Sciences of the United States of America, 106, 12442–12447.PubMedPubMedCentralGoogle Scholar
  10. Carlsson, E., Ding, J. L., & Byrne, B. (2016). SARM modulates MyD88-mediated TLR activation through BB-loop dependent TIR-TIR interactions. Biochimica et Biophysica Acta, 1863, 244–253.PubMedGoogle Scholar
  11. Carty, M., Goodbody, R., Schroder, M., Stack, J., Moynagh, P. N., & Bowie, A. G. (2006). The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nature Immunology, 7, 1074–1081.PubMedGoogle Scholar
  12. Chang, C., Hsieh, Y. W., Lesch, B. J., Bargmann, C. I., & Chuang, C. F. (2011). Microtubule-based localization of a synaptic calcium-signaling complex is required for left-right neuronal asymmetry in C. elegans. Development, 138, 3509–3518.PubMedPubMedCentralGoogle Scholar
  13. Chau, T. L., Gioia, R., Gatot, J. S., Patrascu, F., Carpentier, I., Chapelle, J. P., O’Neill, L., Beyaert, R., Piette, J., & Chariot, A. (2008). Are the IKKs and IKK-related kinases TBK1 and IKK-epsilon similarly activated? Trends in Biochemical Sciences, 33, 171–180.PubMedGoogle Scholar
  14. Chen, C. Y., Lin, C. W., Chang, C. Y., Jiang, S. T., & Hsueh, Y. P. (2011). Sarm1, a negative regulator of innate immunity, interacts with syndecan-2 and regulates neuronal morphology. Journal of Cell Biology, 193, 769–784.PubMedGoogle Scholar
  15. Chiang, A. S., Lin, C. Y., Chuang, C. C., Chang, H. M., Hsieh, C. H., Yeh, C. W., Shih, C. T., Wu, J. J., Wang, G. T., Chen, Y. C., Wu, C. C., Chen, G. Y., Ching, Y. T., Lee, P. C., Lin, C. Y., Lin, H. H., Wu, C. C., Hsu, H. W., Huang, Y. A., Chen, J. Y., Chiang, H. J., Lu, C. F., Ni, R. F., Yeh, C. Y., & Hwang, J. K. (2011). Three-dimensional reconstruction of brain-wide wiring networks in Drosophila at single-cell resolution. Current Biology, 21, 1–11.PubMedGoogle Scholar
  16. Chuang, C. F., & Bargmann, C. I. (2005). A Toll-interleukin 1 repeat protein at the synapse specifies asymmetric odorant receptor expression via ASK1 MAPKKK signaling. Genes & Development, 19, 270–281.Google Scholar
  17. Coban, C., Igari, Y., Yagi, M., Reimer, T., Koyama, S., Aoshi, T., Ohata, K., Tsukui, T., Takeshita, F., Sakurai, K., Ikegami, T., Nakagawa, A., Horii, T., Nunez, G., Ishii, K. J., & Akira, S. (2010). Immunogenicity of whole-parasite vaccines against Plasmodium falciparum involves malarial hemozoin and host TLR9. Cell Host & Microbe, 7, 50–61.Google Scholar
  18. De Gregorio, E., Spellman, P. T., Rubin, G. M., & Lemaitre, B. (2001). Genome-wide analysis of the Drosophila immune response by using oligonucleotide microarrays. Genes & Development, 98, 12590–12595.Google Scholar
  19. Deshmukh, S. D., Kremer, B., Freudenberg, M., Bauer, S., Golenbock, D. T., & Henneke, P. (2011). Macrophages recognize streptococci through bacterial single-stranded RNA. EMBO Reports, 12, 71–76.PubMedGoogle Scholar
  20. Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013). STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 29, 15–21.PubMedGoogle Scholar
  21. Ehrnstrom, B., Beckwith, K. S., Yurchenko, M., Moen, S. H., Kojen, J. F., Lentini, G., Teti, G., Damas, J. K., Espevik, T., & Stenvik, J. (2017). Toll-like receptor 8 is a major sensor of group b streptococcus but not Escherichia coli in human primary monocytes and macrophages. Frontiers in Immunology, 8, 1243.PubMedPubMedCentralGoogle Scholar
  22. El Chamy, L., Leclerc, V., Caldelari, I., & Reichhart, J. M. (2008). Sensing of ‘danger signals’ and pathogen-associated molecular patterns defines binary signaling pathways ‘upstream’ of Toll. Nature Immunology, 9, 1165–1170.PubMedPubMedCentralGoogle Scholar
  23. Feldman, N., Rotter-Maskowitz, A., & Okun, E. (2015). DAMPs as mediators of sterile inflammation in aging-related pathologies. Ageing Research Reviews, 24, 29–39.Google Scholar
  24. Foldi, I., Anthoney, N., Harrison, N., Gangloff, M., Verstak, B., Nallasivan, M. P., AlAhmed, S., Zhu, B., Phizacklea, M., Losada-Perez, M., Moreira, M., Gay, N. J., & Hidalgo, A. (2017). Three-tier regulation of cell number plasticity by neurotrophins and Tolls in Drosophila. Journal of Cell Biology, 216, 1421–1438.PubMedGoogle Scholar
  25. Gerdts, J., Summers, D. W., Sasaki, Y., DiAntonio, A., & Milbrandt, J. (2013). Sarm1-mediated axon degeneration requires both SAM and TIR interactions. The Journal of Neuroscience, 33, 13569–13580.PubMedPubMedCentralGoogle Scholar
  26. Gilmore, T. D. (2006). Introduction to NF-kappaB: players, pathways, perspectives. Oncogene, 25, 6680–6684.PubMedGoogle Scholar
  27. Gobert, V., Gottar, M., Matskevich, A. A., Rutschmann, S., Royet, J., Belvin, M., Hoffmann, J. A., & Ferrandon, D. (2003). Dual activation of the Drosophila toll pathway by two pattern recognition receptors. Science, 302, 2126–2130.PubMedGoogle Scholar
  28. Gorden, K. B., Gorski, K. S., Gibson, S. J., Kedl, R. M., Kieper, W. C., Qiu, X., Tomai, M. A., Alkan, S. S., & Vasilakos, J. P. (2005). Synthetic TLR agonists reveal functional differences between human TLR7 and TLR8. Journal of Immunology, 174, 1259–1268.Google Scholar
  29. Gottar, M., Gobert, V., Matskevich, A. A., Reichhart, J. M., Wang, C., Butt, T. M., Belvin, M., Hoffmann, J. A., & Ferrandon, D. (2006). Dual detection of fungal infections in Drosophila via recognition of glucans and sensing of virulence factors. Cell, 127, 1425–1437.PubMedPubMedCentralGoogle Scholar
  30. Gross, A., Benninger, F., Madar, R., Illouz, T., Griffioen, K., Steiner, I., Offen, D., & Okun, E. (2017). Toll-like receptor 3 deficiency decreases epileptogenesis in a pilocarpine model of SE-induced epilepsy in mice. Epilepsia, 58, 586–596.PubMedGoogle Scholar
  31. Guan, Y., Ranoa, D. R., Jiang, S., Mutha, S. K., Li, X., Baudry, J., & Tapping, R. I. (2010). Human TLRs 10 and 1 share common mechanisms of innate immune sensing but not signaling. Journal of Immunology, 184, 5094–5103.Google Scholar
  32. Haghayeghi, A., Sarac, A., Czerniecki, S., Grosshans, J., & Schock, F. (2010). Pellino enhances innate immunity in Drosophila. Mechanisms of Development, 127, 301–307.PubMedGoogle Scholar
  33. Hashimoto, C., Gerttula, S., & Anderson, K. V. (1991). Plasma membrane localization of the Toll protein in the syncytial Drosophila embryo: importance of transmembrane signaling for dorsal-ventral pattern formation. Development, 111, 1021–1028.PubMedGoogle Scholar
  34. Heil, F., Hemmi, H., Hochrein, H., Ampenberger, F., Kirschning, C., Akira, S., Lipford, G., Wagner, H., & Bauer, S. (2004). Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science, 303, 1526–1529.PubMedGoogle Scholar
  35. Henry, G. L., Davis, F. P., Picard, S., & Eddy, S. R. (2012). Cell type-specific genomics of Drosophila neurons. Nucleic Acids Research, 40, 9691–9704.PubMedPubMedCentralGoogle Scholar
  36. Hidmark, A., von Saint Paul, A., & Dalpke, A. H. (2012). Cutting edge: TLR13 is a receptor for bacterial RNA. Journal of Immunology, 189, 2717–2721.Google Scholar
  37. Hoffmann, J. A. (2003). The immune response of Drosophila. Nature, 426, 33–38.PubMedGoogle Scholar
  38. Huang, H. R., Chen, Z. J., Kunes, S., Chang, G. D., & Maniatis, T. (2010). Endocytic pathway is required for Drosophila Toll innate immune signaling. Proceedings of the National Academy of Sciences of the United States of America, 107, 8322–8327.PubMedPubMedCentralGoogle Scholar
  39. Ip, Y. T., Reach, M., Engstrom, Y., Kadalayil, L., Cai, H., Gonzalez-Crespo, S., Tatei, K., & Levine, M. (1993). Dif, a dorsal-related gene that mediates an immune response in Drosophila. Cell, 75, 753–763.PubMedGoogle Scholar
  40. Irving, P., Troxler, L., Heuer, T. S., Belvin, M., Kopczynski, C., Reichhart, J. M., Hoffmann, J. A., & Hetru, C. (2001). A genome-wide analysis of immune responses in Drosophila. Proceedings of the National Academy of Sciences of the United States of America, 98, 15119–15124.PubMedPubMedCentralGoogle Scholar
  41. Jang, I. H., Chosa, N., Kim, S. H., Nam, H. J., Lemaitre, B., Ochiai, M., Kambris, Z., Brun, S., Hashimoto, C., Ashida, M., Brey, P. T., & Lee, W. J. (2006). A Spatzle-processing enzyme required for toll signaling activation in Drosophila innate immunity. Developmental Cell, 10, 45–55.PubMedGoogle Scholar
  42. Kambris, Z., Brun, S., Jang, I. H., Nam, H. J., Romeo, Y., Takahashi, K., Lee, W. J., Ueda, R., & Lemaitre, B. (2006). Drosophila immunity: a large-scale in vivo RNAi screen identifies five serine proteases required for Toll activation. Current Biology, 16, 808–813.PubMedGoogle Scholar
  43. Kanodia, J. S., Rikhy, R., Kim, Y., Lund, V. K., DeLotto, R., Lippincott-Schwartz, J., & Shvartsman, S. Y. (2009). Dynamics of the dorsal morphogen gradient. Proceedings of the National Academy of Sciences of the United States of America, 106, 21707–21712.PubMedPubMedCentralGoogle Scholar
  44. Kanoh, H., Tong, L. L., Kuraishi, T., Suda, Y., Momiuchi, Y., Shishido, F., & Kurata, S. (2015). Genome-wide RNAi screening implicates the E3 ubiquitin ligase Sherpa in mediating innate immune signaling by Toll in Drosophila adults. Science Signaling, 8, ra107.PubMedGoogle Scholar
  45. Kawai, T., & Akira, S. (2006). TLR signaling. Cell Death & Differentiation, 13, 816–825.Google Scholar
  46. Koblansky, A. A., Jankovic, D., Oh, H., Hieny, S., Sungnak, W., Mathur, R., Hayden, M. S., Akira, S., Sher, A., & Ghosh, S. (2013). Recognition of profilin by Toll-like receptor 12 is critical for host resistance to Toxoplasma gondii. Immunity, 38, 119–130.PubMedGoogle Scholar
  47. Köster, J., & Rahmann, S. (2012). Snakemake—A scalable bioinformatics workflow engine. Bioinformatics, 28, 2520–2522.PubMedGoogle Scholar
  48. Kremer, M. C., Jung, C., Batelli, S., Rubin, G. M., & Gaul, U. (2017). The glia of the adult Drosophila nervous system. Glia, 65, 606–638.PubMedPubMedCentralGoogle Scholar
  49. Kruger, A., Oldenburg, M., Chebrolu, C., Beisser, D., Kolter, J., Sigmund, A. M., Steinmann, J., Schafer, S., Hochrein, H., Rahmann, S., Wagner, H., Henneke, P., Hornung, V., Buer, J., & Kirschning, C. J. (2015). Human TLR8 senses UR/URR motifs in bacterial and mitochondrial RNA. EMBO Reports, 16, 1656–1663.PubMedPubMedCentralGoogle Scholar
  50. Lathia, J. D., Okun, E., Tang, S. C., Griffioen, K., Cheng, A., Mughal, M. R., Laryea, G., Selvaraj, P. K., ffrench-Constant, C., Magnus, T., Arumugam, T. V., & Mattson, M. P. (2008). Toll-like receptor 3 is a negative regulator of embryonic neural progenitor cell proliferation. The Journal of Neuroscience, 28, 13978–13984.PubMedPubMedCentralGoogle Scholar
  51. Ligoxygakis, P., Pelte, N., Hoffmann, J. A., & Reichhart, J. M. (2002). Activation of Drosophila toll during fungal infection by a blood serine protease. Science, 297, 114–116.PubMedGoogle Scholar
  52. Lindsay, S. A., & Wasserman, S. A. (2014). Conventional and non-conventional Drosophila Toll signaling. Developmental & Comparative Immunology, 42, 16–24.Google Scholar
  53. Love, M. I., Huber, W., & Anders, S. (2014). Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology, 15, 550.PubMedPubMedCentralGoogle Scholar
  54. Mancuso, G., Gambuzza, M., Midiri, A., Biondo, C., Papasergi, S., Akira, S., Teti, G., & Beninati, C. (2009). Bacterial recognition by TLR7 in the lysosomes of conventional dendritic cells. Nature Immunology, 10, 587–594.PubMedGoogle Scholar
  55. Manfruelli, P., Reichhart, J. M., Steward, R., Hoffmann, J. A., & Lemaitre, B. (1999). A mosaic analysis in Drosophila fat body cells of the control of antimicrobial peptide genes by the Rel proteins Dorsal and DIF. The EMBO Journal, 18, 3380–3391.PubMedPubMedCentralGoogle Scholar
  56. Martin, M. (2011). Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBNET Journal, 17, 10Google Scholar
  57. Mathur, R., Oh, H., Zhang, D., Park, S. G., Seo, J., Koblansky, A., Hayden, M. S., & Ghosh, S. (2012). A mouse model of Salmonella typhi infection. Cell, 151, 590–602.PubMedPubMedCentralGoogle Scholar
  58. McCarthy, G. M., Bridges, C. R., Blednov, Y. A., & Harris, R. A. 2017. CNS cell-type localization and LPS response of TLR signaling pathways. F1000Res 6, 1144.PubMedPubMedCentralGoogle Scholar
  59. McIlroy, G., Foldi, I., Aurikko, J., Wentzell, J. S., Lim, M. A., Fenton, J. C., Gay, N. J., & Hidalgo, A. (2013). Toll-6 and Toll-7 function as neurotrophin receptors in the Drosophila melanogaster CNS. Nature Neuroscience, 16, 1248–1256.PubMedPubMedCentralGoogle Scholar
  60. McLaughlin, C. N., Nechipurenko, I. V., Liu, N., & Broihier, H. T. (2016). A Toll receptor-FoxO pathway represses Pavarotti/MKLP1 to promote microtubule dynamics in motoneurons. Journal of Cell Biology, 214, 459–474.PubMedGoogle Scholar
  61. Meng, X., Khanuja, B. S., & Ip, Y. T. (1999). Toll receptor-mediated Drosophila immune response requires Dif, an NF-kappaB factor. Genes Dev, 13, 792–797.PubMedPubMedCentralGoogle Scholar
  62. Michel, T., Reichhart, J. M., Hoffmann, J. A., & Royet, J. (2001). Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature, 414, 756–759.PubMedGoogle Scholar
  63. Morisato, D., & Anderson, K. V. (1994). The spatzle gene encodes a component of the extracellular signaling pathway establishing the dorsal-ventral pattern of the Drosophila embryo. Cell, 76, 677–688.PubMedGoogle Scholar
  64. Okun, E., Barak, B., Saada-Madar, R., Rothman, S. M., Griffioen, K. J., Roberts, N., Castro, K., Mughal, M. R., Pita, M. A., Stranahan, A. M., Arumugam, T. V., & Mattson, M. P. (2012). Evidence for a developmental role for TLR4 in learning and memory. PLoS ONE, 7, e47522.PubMedPubMedCentralGoogle Scholar
  65. Okun, E., Griffioen, K., Barak, B., Roberts, N. J., Castro, K., Pita, M. A., Cheng, A., Mughal, M. R., Wan, R., Ashery, U., & Mattson, M. P. (2010a). Toll-like receptor 3 inhibits memory retention and constrains adult hippocampal neurogenesis. Proceedings of the National Academy of Sciences of the United States of America, 107, 15625–15630.PubMedPubMedCentralGoogle Scholar
  66. Okun, E., Griffioen, K. J., & Mattson, M. P. (2011). Toll-like receptor signaling in neural plasticity and disease. Trends in Neurosciences, 34, 269–281.PubMedPubMedCentralGoogle Scholar
  67. Okun, E., Griffioen, K. J., Rothman, S., Wan, R., Cong, W. N., De Cabo, R., Martin-Montalvo, A., Levette, A., Maudsley, S., Martin, B., Arumugam, T. V., & Mattson, M. P. (2014). Toll-like receptors 2 and 4 modulate autonomic control of heart rate and energy metabolism. Brain, Behavior, and Immunity, 36, 90–100.PubMedGoogle Scholar
  68. Okun, E., Griffioen, K. J., Son, T. G., Lee, J. H., Roberts, N. J., Mughal, M. R., Hutchison, E., Cheng, A., Arumugam, T. V., Lathia, J. D., van Praag, H., & Mattson, M. P. (2010b). TLR2 activation inhibits embryonic neural progenitor cell proliferation. Journal of Neurochemistry, 114, 462–474.PubMedPubMedCentralGoogle Scholar
  69. Oldenburg, M., Kruger, A., Ferstl, R., Kaufmann, A., Nees, G., Sigmund, A., Bathke, B., Lauterbach, H., Suter, M., Dreher, S., Koedel, U., Akira, S., Kawai, T., Buer, J., Wagner, H., Bauer, S., Hochrein, H., & Kirschning, C. J. (2012). TLR13 recognizes bacterial 23S rRNA devoid of erythromycin resistance-forming modification. Science, 337, 1111–1115.PubMedGoogle Scholar
  70. Oosenbrug, T., van de Graaff, M. J., Ressing, M. E., & van Kasteren, S.I. (2017). Chemical tools for studying TLR signaling dynamics. Cell Chemical Biology, 24, 801–812.PubMedGoogle Scholar
  71. Osterloh, J. M., Yang, J., Rooney, T. M., Fox, A. N., Adalbert, R., Powell, E. H., Sheehan, A. E., Avery, M. A., Hackett, R., Logan, M. A., MacDonald, J. M., Ziegenfuss, J. S., Milde, S., Hou, Y. J., Nathan, C., Ding, A., Brown, R. H. Jr., Conforti, L., Coleman, M., Tessier-Lavigne, M., Zuchner, S., & Freeman, M. R. (2012). dSarm/Sarm1 is required for activation of an injury-induced axon death pathway. Science, 337, 481–484.PubMedPubMedCentralGoogle Scholar
  72. Parker, J. S., Mizuguchi, K., & Gay, N. J. (2001). A family of proteins related to Spatzle, the toll receptor ligand, are encoded in the Drosophila genome. Proteins, 45, 71–80.PubMedGoogle Scholar
  73. Peng, J., Yuan, Q., Lin, B., Panneerselvam, P., Wang, X., Luan, X. L., Lim, S. K., Leung, B. P., Ho, B., & Ding, J. L. (2010). SARM inhibits both TRIF- and MyD88-mediated AP-1 activation. European Journal of Immunology, 40, 1738–1747.PubMedGoogle Scholar
  74. Rolls, A., Shechter, R., London, A., Ziv, Y., Ronen, A., Levy, R., & Schwartz, M. (2007). Toll-like receptors modulate adult hippocampal neurogenesis. Nature Cell Biology, 9, 1081–1088.PubMedGoogle Scholar
  75. Satoh, T., & Akira, S. (2016). Toll-Like receptor signaling and its inducible proteins. Microbiology Spectrum, 4, 6Google Scholar
  76. Seppo, A., Matani, P., Sharrow, M., & Tiemeyer, M. (2003). Induction of neuron-specific glycosylation by Tollo/Toll-8, a Drosophila Toll-like receptor expressed in non-neural cells. Development, 130, 1439–1448.PubMedGoogle Scholar
  77. Shechter, R., Ronen, A., Rolls, A., London, A., Bakalash, S., Young, M. J., & Schwartz, M. (2008). Toll-like receptor 4 restricts retinal progenitor cell proliferation. Journal of Cell Biology, 183, 393–400.PubMedGoogle Scholar
  78. Stewart, C. R., Stuart, L. M., Wilkinson, K., van Gils, J. M., Deng, J., Halle, A., Rayner, K. J., Boyer, L., Zhong, R., Frazier, W. A., Lacy-Hulbert, A., Khoury, E., Golenbock, J., & Moore, D. T. (2010) CD36 ligands promote sterile inflammation through assembly of a Toll-like receptor 4 and 6 heterodimer. Nature Immunology, 11, 155–161.PubMedGoogle Scholar
  79. Sutcliffe, B., Forero, M. G., Zhu, B., Robinson, I. M., & Hidalgo, A. (2013). Neuron-type specific functions of DNT1, DNT2 and Spz at the Drosophila neuromuscular junction. PLoS ONE, 8, e75902.PubMedPubMedCentralGoogle Scholar
  80. Tabeta, K., Hoebe, K., Janssen, E. M., Du, X., Georgel, P., Crozat, K., Mudd, S., Mann, N., Sovath, S., Goode, J., Shamel, L., Herskovits, A. A., Portnoy, D. A., Cooke, M., Tarantino, L. M., Wiltshire, T., Steinberg, B. E., Grinstein, S., & Beutler, B. (2006). The Unc93b1 mutation 3d disrupts exogenous antigen presentation and signaling via Toll-like receptors 3, 7 and 9. Nature Immunology, 7, 156–164.PubMedGoogle Scholar
  81. Tahoun, A., Jensen, K., Corripio-Miyar, Y., McAteer, S., Smith, D. G. E., McNeilly, T. N., Gally, D. L., & Glass, E. J. (2017). Host species adaptation of TLR5 signalling and flagellin recognition. Scientific Reports, 7, 17677.PubMedPubMedCentralGoogle Scholar
  82. Towb, P., Bergmann, A., & Wasserman, S. A. (2001). The protein kinase Pelle mediates feedback regulation in the Drosophila Toll signaling pathway. Development, 128, 4729–4736.PubMedGoogle Scholar
  83. Ulian-Benitez, S., Bishop, S., Foldi, I., Wentzell, J., Okenwa, C., Forero, M. G., Zhu, B., Moreira, M., Phizacklea, M., McIlroy, G., Li, G., Gay, N. J., & Hidalgo, A. (2017). Kek-6: A truncated-Trk-like receptor for Drosophila neurotrophin 2 regulates structural synaptic plasticity. PLoS Genetics, 13, e1006968.PubMedPubMedCentralGoogle Scholar
  84. Wagner, E. F. (2001). AP-1—Introductory remarks. Oncogene, 20, 2334.PubMedGoogle Scholar
  85. Ward, A., Hong, W., Favaloro, V., & Luo, L. (2015). Toll receptors instruct axon and dendrite targeting and participate in synaptic partner matching in a Drosophila olfactory circuit. Neuron, 85, 1013–1028.PubMedPubMedCentralGoogle Scholar
  86. Wu, C., Chen, Y., Wang, F., Chen, C., Zhang, S., Li, C., Li, W., Wu, S., & Xue, L. (2015). Pelle Modulates dFoxO-Mediated Cell Death in Drosophila. PLoS Genetics, 11, e1005589.PubMedPubMedCentralGoogle Scholar
  87. Yagi, Y., Nishida, Y., & Ip, Y. T. (2010). Functional analysis of Toll-related genes in Drosophila. Development, Growth & Differentiation, 52, 771–783.Google Scholar
  88. Yarovinsky, F., Zhang, D., Andersen, J. F., Bannenberg, G. L., Serhan, C. N., Hayden, M. S., Hieny, S., Sutterwala, F. S., Flavell, R. A., Ghosh, S., & Sher, A. (2005). TLR11 activation of dendritic cells by a protozoan profilin-like protein. Science, 308, 1626–1629.PubMedGoogle Scholar
  89. Zasloff, M. (2002). Antimicrobial peptides of multicellular organisms. Nature, 415, 389–395.PubMedGoogle Scholar
  90. Zhang, Y., Chen, K., Sloan, S. A., Bennett, M. L., Scholze, A. R., O’Keeffe, S., Phatnani, H. P., Guarnieri, P., Caneda, C., Ruderisch, N., Deng, S., Liddelow, S. A., Zhang, C., Daneman, R., Maniatis, T., Barres, B. A., & Wu, J. Q. (2014). An RNA-sequencing transcriptome and splicing database of glia, neurons, and vascular cells of the cerebral cortex. The Journal of Neuroscience, 34, 11929–11947.PubMedPubMedCentralGoogle Scholar
  91. Zhu, B., Pennack, J. A., McQuilton, P., Forero, M. G., Mizuguchi, K., Sutcliffe, B., Gu, C. J., Fenton, J. C., & Hidalgo, A. (2008). Drosophila neurotrophins reveal a common mechanism for nervous system formation. PLoS Biology, 6, e284.PubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.The Mina and Everard Goodman Faculty of Life SciencesBar-Ilan UniversityRamat-GanIsrael
  2. 2.The Mantoux Bioinformatics institute of the Nancy and Stephen Grand Israel National Center for Personalized MedicineWeizmann Institute of ScienceRehovotIsrael
  3. 3.The Leslie and Susan Gonda Multidisciplinary Brain Research CenterBar-Ilan UniversityRamat-GanIsrael
  4. 4.The Paul Feder Laboratory on Alzheimer’s Disease ResearchRamat-GanIsrael
  5. 5.The Mina and Everard Goodman Faculty of Life SciencesBar-Ilan UniversityRamat-GanIsrael

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