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Teneurins instruct synaptic partner matching in an olfactory map

Nature volume 484, pages 201–207 (2012)Cite this article

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Abstract

Neurons are interconnected with extraordinary precision to assemble a functional nervous system. Compared to axon guidance, far less is understood about how individual pre- and postsynaptic partners are matched. To ensure the proper relay of olfactory information in the fruitfly Drosophila, axons of ∼50 classes of olfactory receptor neurons (ORNs) form one-to-one connections with dendrites of ∼50 classes of projection neurons (PNs). Here, using genetic screens, we identified two evolutionarily conserved, epidermal growth factor (EGF)-repeat containing transmembrane Teneurin proteins, Ten-m and Ten-a, as synaptic-partner-matching molecules between PN dendrites and ORN axons. Ten-m and Ten-a are highly expressed in select PN–ORN matching pairs. Teneurin loss- and gain-of-function cause specific mismatching of select ORNs and PNs. Finally, Teneurins promote homophilic interactions in vitro, and Ten-m co-expression in non-partner PNs and ORNs promotes their ectopic connections in vivo. We propose that Teneurins instruct matching specificity between synaptic partners through homophilic attraction.

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Figure 1: PN–ORN synaptic matching screens identify two Teneurins.
Figure 2: Ten-m and Ten-a are differentially expressed in matching PN and ORN classes.
Figure 3: Loss of Teneurins causes PN–ORN mismatching.
Figure 4: Teneurin overexpression in specific PN classes causes mismatching.
Figure 5: Ten-m promotes homophilic interactions in vitro and in vivo.

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References

  1. Sperry, R. W. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc. Natl Acad. Sci. USA 50, 703–710 (1963)

    CAS  Google Scholar 

  2. Dickson, B. J. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002)

    CAS  Google Scholar 

  3. Zipursky, S. L. & Sanes, J. R. Chemoaffinity revisited: dscams, protocadherins, and neural circuit assembly. Cell 143, 343–353 (2010)

    CAS  Google Scholar 

  4. Luo, L. & Flanagan, J. G. Development of continuous and discrete neural maps. Neuron 56, 284–300 (2007)

    CAS  Google Scholar 

  5. Komiyama, T. & Luo, L. Development of wiring specificity in the olfactory system. Curr. Opin. Neurobiol. 16, 67–73 (2006)

    CAS  Google Scholar 

  6. Brochtrup, A. & Hummel, T. Olfactory map formation in the Drosophila brain: genetic specificity and neuronal variability. Curr. Opin. Neurobiol. 21, 85–92 (2011)

    CAS  Google Scholar 

  7. Jefferis, G. S. X. E. et al. Developmental origin of wiring specificity in the olfactory system of Drosophila. Development 131, 117–130 (2003)

    Google Scholar 

  8. Komiyama, T., Sweeney, L. B., Schuldiner, O., Garcia, K. C. & Luo, L. Graded expression of semaphorin-1a cell-autonomously directs dendritic targeting of olfactory projection neurons. Cell 128, 399–410 (2007)

    CAS  Google Scholar 

  9. Hong, W. et al. Leucine-rich repeat transmembrane proteins instruct discrete dendrite targeting in an olfactory map. Nature Neurosci. 12, 1542–1550 (2009)

    CAS  Google Scholar 

  10. Hummel, T. et al. Axonal targeting of olfactory receptor neurons in Drosophila is controlled by Dscam. Neuron 37, 221–231 (2004)

    Google Scholar 

  11. Hummel, T. & Zipursky, S. L. Afferent induction of olfactory glomeruli requires N-cadherin. Neuron 42, 77–88 (2004)

    CAS  Google Scholar 

  12. Sweeney, L. B. et al. Temporal target restriction of olfactory receptor neurons by Semaphorin-1a/PlexinA-mediated axon-axon interactions. Neuron 53, 185–200 (2007)

    CAS  Google Scholar 

  13. Lattemann, M. et al. Semaphorin-1a controls receptor neuron-specific axonal convergence in the primary olfactory center of Drosophila. Neuron 53, 169–184 (2007)

    CAS  Google Scholar 

  14. Chou, Y.-H., Zheng, X., Beachy, P. A. & Luo, L. Patterning axon targeting of olfactory receptor neurons by coupled Hedgehog signaling at two distinct steps. Cell 142, 954–966 (2010)

    CAS  Google Scholar 

  15. Zhu, H. et al. Dendritic patterning by Dscam and synaptic partner matching in the Drosophila antennal lobe. Nature Neurosci. 9, 349–355 (2006)

    CAS  Google Scholar 

  16. Kurusu, M. et al. A screen of cell-surface molecules identifies leucine-rich repeat proteins as key mediators of synaptic target selection. Neuron 59, 972–985 (2008)

    CAS  Google Scholar 

  17. Tucker, R. P. & Chiquet-Ehrismann, R. Teneurins: a conserved family of transmembrane proteins involved in intercellular signaling during development. Dev. Biol. 290, 237–245 (2006)

    CAS  Google Scholar 

  18. Tucker, R. P., Kenzelmann, D., Trzebiatowska, A. & Chiquet-Ehrismann, R. Teneurins: transmembrane proteins with fundamental roles in development. Int. J. Biochem. Cell Biol. 39, 292–297 (2007)

    CAS  Google Scholar 

  19. Young, T. R. & Leamey, C. A. Teneurins: important regulators of neural circuitry. Int. J. Biochem. Cell Biol. 41, 990–993 (2009)

    CAS  Google Scholar 

  20. Baumgartner, S. & Chiquet-Ehrismann, R. Tena, a Drosophila gene related to tenascin, shows selective transcript localization. Mech. Dev. 40, 165–176 (1993)

    CAS  Google Scholar 

  21. Baumgartner, S., Martin, D., Hagios, C. & Chiquet-Ehrismann, R. Tenm, a Drosophila gene related to tenascin, is a new pair-rule gene. EMBO J. 13, 3728–3740 (1994)

    CAS  Google Scholar 

  22. Psychiatric GWAS Consortium Bipolar Disorder Working Group. Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nature Genet. 43, 977–983 (2011)

  23. Levine, A. et al. odd Oz: a novel Drosophila pair rule gene. Cell 77, 587–598 (1994)

    CAS  Google Scholar 

  24. Zheng, L. et al. Drosophila Ten-m and Filamin affect motor neuron growth cone guidance. PLoS ONE 6, e22956 (2011)

    CAS  Google Scholar 

  25. Liebl, F. L. W. et al. Genome-wide P-element screen for Drosophila synaptogenesis mutants. J. Neurobiol. 66, 332–347 (2006)

    CAS  Google Scholar 

  26. Mosca, T. J., Hong, W., Dani, V. S., Favaloro, V. & Luo, L. Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice. Naturehttp://dx.doi.org/10.1038/nature10923 (this issue)

  27. Li, H., Bishop, K. M. & O’Leary, D. D. M. Potential target genes of EMX2 include Odz/Ten-M and other gene families with implications for cortical patterning. Mol. Cell. Neurosci. 33, 136–149 (2006)

    CAS  Google Scholar 

  28. Rubin, B. P., Tucker, R. P., Brown-Luedi, M., Martin, D. & Chiquet-Ehrismann, R. Teneurin 2 is expressed by the neurons of the thalamofugal visual system in situ and promotes homophilic cell-cell adhesion in vitro. Development 129, 4697–4705 (2002)

    CAS  Google Scholar 

  29. Oohashi, T. et al. Mouse Ten-m/Odz is a new family of dimeric type II transmembrane proteins expressed in many tissues. J. Cell Biol. 145, 563–577 (1999)

    CAS  Google Scholar 

  30. Potter, C. J., Tasic, B., Russler, E. V., Liang, L. & Luo, L. The Q system: a repressible binary system for transgene expression, lineage tracing, and mosaic analysis. Cell 141, 536–548 (2010)

    CAS  Google Scholar 

  31. Jefferis, G. S., Marin, E. C., Stocker, R. F. & Luo, L. Target neuron prespecification in the olfactory map of Drosophila. Nature 414, 204–208 (2001)

    CAS  Google Scholar 

  32. Endo, K., Aoki, T., Yoda, Y., Kimura, K.-I. & Hama, C. Notch signal organizes the Drosophila olfactory circuitry by diversifying the sensory neuronal lineages. Nature Neurosci. 10, 153–160 (2007)

    CAS  Google Scholar 

  33. Drescher, U. et al. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 82, 359–370 (1995)

    CAS  Google Scholar 

  34. Cheng, H. J., Nakamoto, M., Bergemann, A. D. & Flanagan, J. G. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82, 371–381 (1995)

    CAS  Google Scholar 

  35. Feldheim, D. A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563–574 (2000)

    CAS  Google Scholar 

  36. Yamagata, M. & Sanes, J. R. Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature 451, 465–469 (2008)

    CAS  Google Scholar 

  37. Shinza-Kameda, M., Takasu, E., Sakurai, K., Hayashi, S. & Nose, A. Regulation of layer-specific targeting by reciprocal expression of a cell adhesion molecule, Capricious. Neuron 49, 205–213 (2006)

    CAS  Google Scholar 

  38. Shishido, E., Takeichi, M. & Nose, A. Drosophila synapse formation: regulation by transmembrane protein with Leu-rich repeats, CAPRICIOUS. Science 280, 2118–2121 (1998)

    CAS  Google Scholar 

  39. de Wit, J., Hong, W., Luo, L. & Ghosh, A. Role of leucine-rich repeat proteins in the development and function of neural circuits. Annu. Rev. Cell Dev. Biol. 27, 697–729 (2011)

    CAS  Google Scholar 

  40. Shen, K., Fetter, R. D. & Bargmann, C. I. Synaptic specificity is generated by the synaptic guidepost protein SYG-2 and its receptor, SYG-1. Cell 116, 869–881 (2004)

    CAS  Google Scholar 

  41. McLaughlin, T., Torborg, C. L., Feller, M. B. & O'Leary, D. D. M. Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40, 1147–1160 (2003)

    CAS  Google Scholar 

  42. Pfeiffenberger, C., Yamada, J. & Feldheim, D. A. Ephrin-As and patterned retinal activity act together in the development of topographic maps in the primary visual system. J. Neurosci. 26, 12873–12884 (2006)

    CAS  Google Scholar 

  43. Imai, T. et al. Pre-target axon sorting establishes the neural map topography. Science 325, 585–590 (2009)

    CAS  Google Scholar 

  44. Serizawa, S. et al. A neuronal identity code for the odorant receptor-specific and activity-dependent axon sorting. Cell 127, 1057–1069 (2006)

    CAS  Google Scholar 

  45. Couto, A., Alenius, M. & Dickson, B. J. Molecular, anatomical, and functional organization of the Drosophila olfactory system. Curr. Biol. 15, 1535–1547 (2005)

    CAS  Google Scholar 

  46. van der Goes van Naters, W. & Carlson, J. R. Receptors and neurons for fly odors in Drosophila. Curr. Biol. 17, 606–612 (2007)

    CAS  Google Scholar 

  47. Leamey, C. A. et al. Ten_m3 regulates eye-specific patterning in the mammalian visual pathway and is required for binocular vision. PLoS Biol. 5, e241 (2007)

    Google Scholar 

  48. Zhu, H. & Luo, L. Diverse functions of N-cadherin in dendritic and axonal terminal arborization of olfactory projection neurons. Neuron 42, 63–75 (2004)

    CAS  Google Scholar 

  49. Kurtovic, A., Widmer, A. & Dickson, B. J. A single class of olfactory neurons mediates behavioural responses to a Drosophila sex pheromone. Nature 446, 542–546 (2007)

    CAS  Google Scholar 

  50. Newsome, T. P., Asling, B. & Dickson, B. J. Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics. Development 127, 851–860 (2000)

    CAS  Google Scholar 

  51. Bohm, R. A. et al. A genetic mosaic approach for neural circuit mapping in Drosophila. Proc. Natl Acad. Sci. USA 107, 16378–16383 (2010)

    CAS  Google Scholar 

  52. Toba, G. et al. The gene search system. A method for efficient detection and rapid molecular identification of genes in Drosophila melanogaster. Genetics 151, 725–737 (1999)

    CAS  Google Scholar 

  53. Dietzl, G. et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 448, 151–156 (2007)

    CAS  Google Scholar 

  54. Hayashi, S. et al. GETDB, a database compiling expression patterns and molecular locations of a collection of Gal4 enhancer traps. Genesis 34, 58–61 (2002)

    CAS  Google Scholar 

  55. Fascetti, N. & Baumgartner, S. Expression of Drosophila Ten-a, a dimeric receptor during embryonic development. Mech. Dev. 114, 197–200 (2002)

    CAS  Google Scholar 

  56. Kinel-Tahan, Y., Weiss, H., Dgany, O., Levine, A. & Wides, R. Drosophila odz gene is required for multiple cell types in the compound retina. Dev. Dyn. 236, 2541–2554 (2007)

    CAS  Google Scholar 

  57. Tea, J. S., Chihara, T. & Luo, L. Histone deacetylase Rpd3 regulates olfactory projection neuron dendrite targeting via the transcription factor Prospero. J. Neurosci. 30, 9939–9946 (2010)

    CAS  Google Scholar 

  58. Markstein, M., Pitsouli, C., Villalta, C., Celniker, S. E. & Perrimon, N. Exploiting position effects and the gypsy retrovirus insulator to engineer precisely expressed transgenes. Nature Genet. 40, 476 (2008)

    CAS  Google Scholar 

  59. Bischof, J., Maeda, R. K., Hediger, M., Karch, F. & Basler, K. An optimized transgenesis system for Drosophila using germ-line-specific φC31 integrases. Proc. Natl Acad. Sci. USA 104, 3312–3317 (2007)

    CAS  Google Scholar 

  60. Venken, K. J. T. et al. Versatile P[acman] BAC libraries for transgenesis studies in Drosophila melanogaster. Nature Methods 6, 431–434 (2009)

    CAS  Google Scholar 

  61. Venken, K. J. T., He, Y., Hoskins, R. A. & Bellen, H. J. P[acman]: a BAC transgenic platform for targeted insertion of large DNA fragments in D. melanogaster. Science 314, 1747–1751 (2006)

    CAS  Google Scholar 

  62. Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22, 451–461 (1999)

    CAS  Google Scholar 

  63. Wu, J. S. & Luo, L. A protocol for dissecting Drosophila melanogaster brains for live imaging or immunostaining. Nature Protocols 1, 2110–2115 (2006)

    CAS  Google Scholar 

  64. Rakovitsky, N. et al. Drosophila Ten-a is a maternal pair-rule and patterning gene. Mech. Dev. 124, 911–924 (2007)

    CAS  Google Scholar 

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Acknowledgements

We thank V. Favaloro for advice on biochemistry and D. Luginbuhl for technical assistance; K. Zinn for the EP collection; H. Zhu for the initial contribution; R. Wides and S. Baumgartner for teneurin reagents; B. Zhang, Bloomington, Kyoto, Harvard and Vienna Stock Centers for fly stocks; BestGene for injection service; and K. Shen, T. Clandinin, D. Berns, V. Favaloro, X. Gao, S. Hippenmeyer, C. Liu, K. Miyamichi and X. Yu for critiques. Supported by a National Institutes of Health (NIH) grant (R01 DC-005982 to L.L.), and Epilepsy, Neonatology and Developmental Biology Training Grants (NIH 5T32 NS007280 and HD007249 to T.J.M.). L.L. is an investigator of the Howard Hughes Medical Institute.

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  1. Department of Biology, Howard Hughes Medical Institute, Stanford University, Stanford, 94305, California, USA

    Weizhe Hong, Timothy J. Mosca & Liqun Luo

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  1. Weizhe Hong
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W.H. designed and performed all experiments. T.J.M. assisted in some experiments. L.L. supervised the project. W.H. and L.L. wrote the manuscript with feedback from T.J.M.

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Correspondence to Liqun Luo.

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Hong, W., Mosca, T. & Luo, L. Teneurins instruct synaptic partner matching in an olfactory map. Nature 484, 201–207 (2012). https://doi.org/10.1038/nature10926

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