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Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline

Nature Neuroscience volume 6, pages 223–230 (2003)Cite this article

Abstract

Neuronal connectivity is established by the axo-dendritic polarity, correct guidance and targeting of neurons. Unlike for axons, the mechanisms responsible for directed outgrowth of dendrites are not well understood. Using single-cell labeling, we describe specific guidance defects in dendrites of identified neurons in frazzled, robo, netrin and commissureless mutant embryos of Drosophila melanogaster. We found that the cell-surface molecules Frazzled and Robo work as guidance molecules not only for axons but also for dendrites as they navigate within the CNS. Furthermore, we report that each neuron showed a cell-autonomous and independent use of guidance molecules.

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Figure 1: Three identified neurons.
Figure 2: Axonal guidance defects.
Figure 3: Dendritic guidance defects.
Figure 4: Summary of guidance defects and their rescue.
Figure 5: Cell-specific rescues.
Figure 6: Frazzled and Robo proteins.

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References

  1. Craig, A.M. & Banker, G. Neuronal polarity. Annu. Rev. Neurosci. 17, 267–310 (1994).

    Article  CAS  Google Scholar 

  2. Luo, L. Rho GTPases in neuronal morphogenesis. Nat. Rev. Neurosci. 1, 173–180 (2000).

    Article  CAS  Google Scholar 

  3. Wu, G.-Y. & Cline, H.T. Stabilization of dendritic arbor structure in vivo by CaMKII. Science 279, 222–226 (1998).

    Article  CAS  Google Scholar 

  4. Tessier-Lavigne, M. & Goodman, C.S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    Article  CAS  Google Scholar 

  5. Chisholm, A. & Tessier-Lavigne, M. Conservation and divergence of axon guidance mechanisms. Curr. Opin. Neurobiol. 9, 603–615 (1999).

    Article  CAS  Google Scholar 

  6. Song, H.J. & Poo, M.M. Signal transduction underlying growth cone guidance by diffusible factors. Curr. Opin. Neurobiol. 9, 355–363 (1999).

    Article  CAS  Google Scholar 

  7. Gao, F.B., Brenman, J.E., Jan, L.Y. & Jan, Y.N. Genes regulating dendritic outgrowth, branching, and routing in Drosophila. Genes Dev. 13, 2549–2561 (1999).

    Article  CAS  Google Scholar 

  8. Polleux, F., Morrow, T. & Ghosh, A. Semaphorin 3A is a chemoattractant for cortical apical dendrites. Nature 404, 567–573 (2000).

    Article  CAS  Google Scholar 

  9. Godenschwege, T.A. et al. Ectopic expression in the giant fiber system of Drosophila reveals distinct roles for Roundabout (Robo), Robo2 and Robo3 in dendritic guidance and synaptic connectivity. J. Neurosci. 22, 3117–3129 (2002).

    Article  CAS  Google Scholar 

  10. Wu, G.Y., Zou, D.J., Rajan, I. & Cline, H. Dendritic dynamics in vivo change during neuronal maturation. J. Neurosci. 19, 4472–4483 (1999).

    Article  CAS  Google Scholar 

  11. Kennedy, T.E., Serafini, T., de la Torre, J.R. & Tessier-Lavigne, M. Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord. Cell 78, 425–435 (1994).

    Article  CAS  Google Scholar 

  12. Culotti, J.G. & Merz, D.C. DCC and netrins. Curr. Opin. Cell Biol. 10, 609–613 (1998).

    Article  CAS  Google Scholar 

  13. Merz, D., Zheng, H., Killeen, M., Krizus, A. & Culotti, J. Multiple signaling mechanisms of the UNC-6/netrin receptors UNC-5 and UNC-40/DCC in vivo. Genetics 158, 1071–1080 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Kidd, T. et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92, 205–215 (1998).

    Article  CAS  Google Scholar 

  15. Kidd, T., Bland, K.S. & Goodman, C.S. Slit is the midline repellent for the Robo receptor in Drosophila. Cell 96, 785–794 (1999).

    Article  CAS  Google Scholar 

  16. Brose, K. et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795–806 (1999).

    Article  CAS  Google Scholar 

  17. Stein, E. & Tessier-Lavigne, M. Hierarchical organization of guidance receptors: silencing of netrin attraction by slit through a Robo/DCC receptor complex. Science 291, 1928–1938 (2001).

    Article  CAS  Google Scholar 

  18. Tear, G., et al. Commissureless controls growth cone guidance across the CNS midline in Drosophila and encodes a novel membrane protein. Neuron 16, 501–514 (1996).

    Article  CAS  Google Scholar 

  19. Keleman, K. et al. Comm sorts robo to control axon guidance at the Drosophila midline. Cell 110, 415–427 (2002).

    Article  CAS  Google Scholar 

  20. Georgiou, M. & Tear, G. Commissureless is required both in commissural neurones and midline cells for axon guidance across the midline. Development 129, 2947–2956 (2002).

    CAS  PubMed  Google Scholar 

  21. Chiba, A. Early development of Drosophila neuromuscular junction: a model for studying neuronetwork development. Intl. Rev. Neurobiol. 43, 1–24 (1999).

    Article  CAS  Google Scholar 

  22. Seeger, M., Tear, G., Ferres-Marco, D. & Goodman, C.S. Mutations affecting growth cone guidance in Drosophila: genes necessary for guidance toward or away from the midline. Neuron 10, 409–426 (1993).

    Article  CAS  Google Scholar 

  23. Wolf, B.D. & Chiba, A. Axon pathfinding proceeds normally despite disrupted growth cone decisions at CNS midline. Development 127, 2001–2009 (2000).

    CAS  PubMed  Google Scholar 

  24. Mitchell, K.J., et al. Genetic analysis of netrin genes in Drosophila: netrins guide CNS commissurral axons and peripheral motor axons. Neuron 17, 203–215 (1996).

    Article  CAS  Google Scholar 

  25. Harris, R., Sabatelli, L. & Seeger, M. Guidance cues at the Drosophila CNS midline: identification and characterization of two Drosophila Netrin/UNC-6 homologs. Neuron 17, 217–228 (1996).

    Article  CAS  Google Scholar 

  26. Kolodziej, P.A. et al. Frazzled encodes a Drosophila member of the DCC immunoglobulin subfamily and is required for CNS and motor axon guidance. Cell 87, 197–204 (1996).

    Article  CAS  Google Scholar 

  27. Hiramoto, M., Hiromi, Y., Giniger, E. & Hotta, Y. The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution. Nature 406, 886–889 (2000).

    Article  CAS  Google Scholar 

  28. Battye, R., Stevens, A. & Jacobs, J.R. Axon repulsion from the midline of the Drosophila CNS requires slit function. Development 126, 2475–2481 (1999).

    CAS  PubMed  Google Scholar 

  29. Wharton, K.A., Jr. & Crews, S.T. CNS midline enhancers of the Drosophila slit and Toll genes. Mech. Dev. 40, 141–154 (1993).

    Article  CAS  Google Scholar 

  30. Rothberg, J.M., Jacobs, J.R., Goodman, C.S. & Artavanis-Tsakonas, S. Slit: an extracellular protein necessary for development of midline glia and commissural axon pathways contains both EGF and LRR domains. Genes Dev. 4, 2169–2187 (1990).

    Article  CAS  Google Scholar 

  31. Simpson, J., Bland, K., Fetter, R. & Goodman, C. Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position. Cell 103, 1019–1032 (2000).

    Article  CAS  Google Scholar 

  32. Rajagopalan, S., Vivancos, V., Nicolas, E. & Dickson, B. Selecting a longitudinal pathway: Robo receptors specify the lateral position of axons in the Drosophila CNS. Cell 103, 1033–1045 (2000).

    Article  CAS  Google Scholar 

  33. Whitford, K.L. et al. Regulation of cortical dendrite development by Slit-Robo interactions. Neuron 33, 47–61 (2002).

    Article  CAS  Google Scholar 

  34. Li, Z., Van Aelst, L. & Cline, H.T. Rho GTPases regulate distinct aspects of dendritic arbor growth in Xenopus central neurons in vivo. Nat. Neurosci. 3, 217–225 (2000).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  36. Sweeney, N.T., Wenjun, L. & Gao, F-B. Genetic manipulation of single neurons in vivo reveals specific roles of flamingo in neuronal morphogenesis. Dev. Biol. 247, 76–88 (2002).

    Article  CAS  Google Scholar 

  37. Landgraf, M., Bossing, T., Technau, G.M. & Bate, M. The origin, location and projections of the embryonic abdominal motoneurons of Drosophila. J. Neurosci. 17, 9642–9655 (1997).

    Article  CAS  Google Scholar 

  38. Bashaw, G.J. & Goodman, C.S. Chimeric axon guidance receptors: the cytoplasmic domains of slit and netrin receptors specify attraction versus repulsion. Cell 97, 917–926 (1999).

    Article  CAS  Google Scholar 

  39. Wolf, B., Seeger, M.A. & Chiba, A. Commissureless endocytosis is correlated with initiation of neuromuscular synaptogenesis. Development 125, 3853–3863 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the current members of the Chiba lab, T. Godenschwege and R. Murphey (University of Massachusetts) for comments on the manuscript. We also thank M. Mussacchio (University of Illinois) for help during the early phase of data collection. This work was supported by a postdoctoral fellowship from Association pour la Recherche sur le Cancer to M.P.F. and grants from the National Institutes of Health/NINDS (NS350049, NS40420) and the National Science Foundation (IBN 9986067) to A.C.

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  1. Marie-Pierre Furrer and Susan Kim: The first two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Cell and Structural Biology, University of Illinois, 601 South Goodwin Avenue, Urbana, 61801, Illinois, USA

    Marie-Pierre Furrer, Susan Kim, Brian Wolf & Akira Chiba

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  1. Marie-Pierre Furrer
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Correspondence to Akira Chiba.

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Furrer, MP., Kim, S., Wolf, B. et al. Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline. Nat Neurosci 6, 223–230 (2003). https://doi.org/10.1038/nn1017

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