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.

  • Article
  • Published:

Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections

Nature Neuroscience volume 15, pages 871–875 (2012)Cite this article

Subjects

Abstract

Fic domains can catalyze the addition of adenosine monophosphate to target proteins. To date, the function of Fic domain proteins in eukaryotic physiology remains unknown. We generated genetic models of the single Drosophila Fic domain–containing protein, Fic. Flies lacking Fic were viable and fertile, but blind. Photoreceptor cells depolarized normally following light stimulation, but failed to activate postsynaptic neurons, as indicated by the loss of ON transients in electroretinograms, consistent with a neurotransmission defect. Functional rescue of neurotransmission required expression of enzymatically active Fic on capitate projections of glia cells, but not neurons, supporting a role in the recycling of the visual neurotransmitter histamine. Histamine levels were reduced in the lamina of Fic null flies, and dietary histamine partially restored ON transients. These findings establish a previously unknown regulatory mechanism in visual neurotransmission and provide, to the best of our knowledge, the first evidence for a role of glial capitate projections in neurotransmitter recycling.

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: Fic is required for visual neurotransmission.
Figure 2: Visual neurotransmission requires Fic enzymatic activity in glia cells.
Figure 3: Fic is required for recycling of the histamine neurotransmitter.
Figure 4: Fic active site is extracellular and localizes to capitate projections.

Similar content being viewed by others

References

  1. Yarbrough, M.L. et al. AMPylation of Rho GTPases by Vibrio VopS disrupts effector binding and downstream signaling. Science 323, 269–272 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Brown, M.S., Segal, A. & Stadtman, E.R. Modulation of glutamine synthetase adenylylation and deadenylylation is mediated by metabolic transformation of the P II regulatory protein. Proc. Natl. Acad. Sci. USA 68, 2949–2953 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Broberg, C.A. & Orth, K. Tipping the balance by manipulating post-translational modifications. Curr. Opin. Microbiol. 13, 34–40 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Müller, M.P. et al. The Legionella effector protein DrrA AMPylates the membrane traffic regulator Rab1b. Science 329, 946–949 (2010).

    Article  PubMed  Google Scholar 

  5. Worby, C.A. et al. The fic domain: regulation of cell signaling by adenylylation. Mol. Cell 34, 93–103 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kinch, L.N., Yarbrough, M.L., Orth, K. & Grishin, N.V. Fido, a novel AMPylation domain common to fic, doc, and AvrB. PLoS ONE 4, e5818 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Benzer, S. Behavioral mutants of Drosophila isolated by countercurrent distribution. Proc. Natl. Acad. Sci. USA 58, 1112–1119 (1967).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Melzig, J. et al. Genetic depletion of histamine from the nervous system of Drosophila eliminates specific visual and mechanosensory behavior. J. Comp. Physiol. A 179, 763–773 (1996).

    Article  CAS  PubMed  Google Scholar 

  9. Alawi, A.A. & Pak, W.L. On-transient of insect electroretinogram: its cellular origin. Science 172, 1055–1057 (1971).

    Article  CAS  PubMed  Google Scholar 

  10. Heisenberg, M. Separation of receptor and lamina potentials in the electroretinogram of normal and mutant Drosophila. J. Exp. Biol. 55, 85–100 (1971).

    CAS  PubMed  Google Scholar 

  11. Stowers, R.S. & Schwarz, T.L. A genetic method for generating Drosophila eyes composed exclusively of mitotic clones of a single genotype. Genetics 152, 1631–1639 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Pantazis, A. et al. Distinct roles for two histamine receptors (hclA and hclB) at the Drosophila photoreceptor synapse. J. Neurosci. 28, 7250–7259 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stowers, R.S., Megeath, L.J., Gorska-Andrzejak, J., Meinertzhagen, I.A. & Schwarz, T.L. Axonal transport of mitochondria to synapses depends on milton, a novel Drosophila protein. Neuron 36, 1063–1077 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Fabian-Fine, R. et al. Endophilin promotes a late step in endocytosis at glial invaginations in Drosophila photoreceptor terminals. J. Neurosci. 23, 10732–10744 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lin, D.M. & Goodman, C.S. Ectopic and increased expression of Fasciclin II alters motoneuron growth cone guidance. Neuron 13, 507–523 (1994).

    Article  CAS  PubMed  Google Scholar 

  16. Sepp, K.J., Schulte, J. & Auld, V.J. Peripheral glia direct axon guidance across the CNS/PNS transition zone. Dev. Biol. 238, 47–63 (2001).

    Article  CAS  PubMed  Google Scholar 

  17. Zhu, Y., Nern, A., Zipursky, S.L. & Frye, M.A. Peripheral visual circuits functionally segregate motion and phototaxis behaviors in the fly. Curr. Biol. 19, 613–619 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gavin, B.A., Arruda, S.E. & Dolph, P.J. The role of carcinine in signaling at the Drosophila photoreceptor synapse. PLoS Genet. 3, e206 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Melzig, J., Burg, M., Gruhn, M., Pak, W.L. & Buchner, E. Selective histamine uptake rescues photo- and mechanoreceptor function of histidine decarboxylase–deficient Drosophila mutant. J. Neurosci. 18, 7160–7166 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wagner, S. et al. Drosophila photoreceptors express cysteine peptidase tan. J. Comp. Neurol. 500, 601–611 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Burg, M.G., Sarthy, P.V., Koliantz, G. & Pak, W.L. Genetic and molecular identification of a Drosophila histidine decarboxylase gene required in photoreceptor transmitter synthesis. EMBO J. 12, 911–919 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Borycz, J.A., Borycz, J., Kubow, A., Kostyleva, R. & Meinertzhagen, I.A. Histamine compartments of the Drosophila brain with an estimate of the quantum content at the photoreceptor synapse. J. Neurophysiol. 93, 1611–1619 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Richardt, A., Rybak, J., Stortkuhl, K.F., Meinertzhagen, I.A. & Hovemann, B.T. Ebony protein in the Drosophila nervous system: optic neuropile expression in glial cells. J. Comp. Neurol. 452, 93–102 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Richardt, A. et al. Ebony, a novel nonribosomal peptide synthetase for beta-alanine conjugation with biogenic amines in Drosophila. J. Biol. Chem. 278, 41160–41166 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Romero-Calderón, R. et al. A glial variant of the vesicular monoamine transporter is required to store histamine in the Drosophila visual system. PLoS Genet. 4, e1000245 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  26. Edwards, T.N. & Meinertzhagen, I.A. The functional organisation of glia in the adult brain of Drosophila and other insects. Prog. Neurobiol. 90, 471–497 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Borycz, J., Borycz, J.A., Loubani, M. & Meinertzhagen, I.A. tan and ebony genes regulate a novel pathway for transmitter metabolism at fly photoreceptor terminals. J. Neurosci. 22, 10549–10557 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sunio, A., Metcalf, A.B. & Kramer, H. Genetic dissection of endocytic trafficking in Drosophila using a horseradish peroxidase–bride of sevenless chimera: hook is required for normal maturation of multivesicular endosomes. Mol. Biol. Cell 10, 847–859 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Stark, W.S. & Carlson, S.D. Ultrastructure of capitate projections in the optic neuropil of Diptera. Cell Tissue Res. 246, 481–486 (1986).

    Article  CAS  PubMed  Google Scholar 

  30. Meinertzhagen, I.A. & Wang, Y. Drosophila mutants tan and ebony have altered numbers of capitate projections, glial invaginations into photoreceptor terminals. in Neurobiology: From Membrane to Mmind, vol II (eds. N. Elsner & H. Wässle) 457 (Georg Thieme Verlag, Stutgart, 1997).

  31. Tan, Y. & Luo, Z.Q. Legionella pneumophila SidD is a deAMPylase that modifies Rab1. Nature 475, 506–509 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Neunuebel, M.R. et al. De-AMPylation of the small GTPase Rab1 by the pathogen Legionella pneumophila. Science 333, 453–456 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mukherjee, S. et al. Modulation of Rab GTPase function by a protein phosphocholine transferase. Nature 477, 103–106 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Engel, P. et al. Adenylylation control by intra- or intermolecular active-site obstruction in Fic proteins. Nature 482, 107–110 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Rost, B., Yachdav, G. & Liu, J. The PredictProtein server. Nucleic Acids Res. 32, W321–326 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Williamson, W.R., Wang, D., Haberman, A.S. & Hiesinger, P.R. A dual function of V0-ATPase a1 provides an endolysosomal degradation mechanism in Drosophila melanogaster photoreceptors. J. Cell Biol. 189, 885–899 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Akbar, M.A., Ray, S. & Kramer, H. The SM protein Car/Vps33A regulates SNARE-mediated trafficking to lysosomes and lysosome-related organelles. Mol. Biol. Cell 20, 1705–1714 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Sharma, A., Mariappan, M., Appathurai, S. & Hegde, R.S. In vitro dissection of protein translocation into the mammalian endoplasmic reticulum. Methods Mol. Biol. 619, 339–363 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We are grateful to R. Hiesinger for help and advice with the ERG measurements and the use of his ERG setup, W. Pak, B. Hoveman and the Bloomington Stock center for fly lines, M. Buszczak for antibodies, C. Gilpin from the Molecular and Cellular Imaging Facility at UT Southwestern, S.H. Kim and B. Tu for technical help, and to E. Kavalali and A. Haberman for helpful discussions. This work was supported by grants to H.K. from the US National Institutes of Health National Eye Institute (EY10199 and EY021922) and Visual Science Core grant EY020799. K.O. and H.H. are supported by grants from the US National Institutes of Health (Allergy and Infectious Disease, R01-AI056404 and R01-AI087808) and the Welch Foundation (I-1561). K.O. is a Burroughs Wellcome Investigator in Pathogenesis of Infectious Disease and a W.W. Caruth Jr. Biomedical Scholar.

Author information

Authors and Affiliations

  1. Department of Neuroscience, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Mokhlasur Rahman, Xinran Liu, Yoshie Sugiura & Helmut Krämer

  2. Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Hyeilin Ham & Kim Orth

  3. Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Helmut Krämer

Authors
  1. Mokhlasur Rahman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hyeilin Ham
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xinran Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yoshie Sugiura
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kim Orth
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Helmut Krämer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

M.R. and H.K. performed the fly genetic studies. X.L. and Y.S. performed the electron microscopy studies. H.H. performed the molecular biology and biochemistry studies. H.K., M.R. and K.O. designed the study and analyzed the data. H.K. and K.O. wrote the paper. All of the authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Helmut Krämer.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figure 1 and Supplementary Table 1 (PDF 7650 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rahman, M., Ham, H., Liu, X. et al. Visual neurotransmission in Drosophila requires expression of Fic in glial capitate projections. Nat Neurosci 15, 871–875 (2012). https://doi.org/10.1038/nn.3102

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nn.3102

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