Axon routing across the midline controlled by the Drosophila Derailed receptor

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In nervous systems with symmetry about the midline, many neurons project axons from one side to the other. Although several of the components controlling midline crossing have been identified1,2,3,4, little is known about how axons choose the appropriate pathway when crossing. For example, in the Drosophila embryo axons cross the midline in one of two distinct tracts, the anterior or posterior commissure (AC or PC, respectively). Here we show that the Derailed (Drl) receptor tyrosine kinase is expressed by neurons that project in the AC, and that in the absence of Drl such neurons often project abnormally into the PC. Conversely, misexpression of Drl in PC neurons forces them to cross in the AC. The behaviour of Drl-misexpressing neurons and the in vivo binding pattern of a soluble Drl receptor probe indicate that Drl acts as a guidance receptor for a repellent ligand present in the PC. Our results show that Drl is a novel component in the control of midline crossing.

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Figure 1: Drl is required for proper projection of anterior commissure axons across the midline.
Figure 2: Drl switches axons from the PC to the AC.
Figure 3: Drl recognizes a repulsive cue in the PC.


  1. 1

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

  2. 2

    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).

  3. 3

    Kidd,T., Russell,C., Goodman,C. S. & Tear,G. Dosage-sensitive and complementary functions of roundabout and commissureless control axon crossing of the CNS midline. Neuron 20, 25–33 (1998).

  4. 4

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

  5. 5

    Callahan,C. A., Muralidhar,M. G., Lundgren, S. E., Scully,A. L. & Thomas,J. B. Control of neuronal pathway selection by a Drosophila receptor protein-tyrosine kinase family member. Nature 376, 171–174 ( 1995).

  6. 6

    Bonkowsky,J. L. & Thomas,J. B. Cell-type specific modular regulation of derailed in the Drosophila nervous system. Mech. Dev. 82, 181–184 (1999).

  7. 7

    Crews,S. T., Thomas,J. B. & Goodman, C. S. The Drosophila single-minded gene encodes a nuclear protein with sequence similarity to the per gene product. Cell 52, 143–151 (1988).

  8. 8

    Klämbt,C., Jacobs,J. R. & Goodman, C. S. The midline of the Drosophila central nervous system: a model for the genetic analysis of cell fate, cell migration, and growth cone guidance. Cell 64, 801– 815 (1991).

  9. 9

    Thor,S. & Thomas,J. B. The Drosophila islet gene governs axon pathfinding and neurotransmitter identity. Neuron 18, 397–409 ( 1997).

  10. 10

    Thor,S., Andersson,S. G., Tomlinson, A. & Thomas,J. B. A LIM-homeodomain combinatorial code for motor-neuron pathway selection. Nature 397, 76–80 ( 1999).

  11. 11

    Callahan,C. A. & Thomas,J. B. Tau–β-galactosidase, an axon-targeted fusion protein. Proc. Natl Acad. Sci. USA 91, 5972–5976 (1994).

  12. 12

    Brand,A. H. & Perrimon,N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118, 401–415 ( 1993).

  13. 13

    Dittrich,R., Bossing,T., Gould,A. P., Technau,G. M. & Urban, J. The differentiation of the serotonergic neurons in the Drosophila ventral nerve cord depends on the combined function of the zinc finger proteins Eagle and Huckebein. Development 124, 2515–2525 (1997).

  14. 14

    Higashijima,S., Shishido,E., Matsuzaki,M. & Saigo,K. eagle, a member of the steroid receptor gene superfamily, is expressed in a subset of neuroblasts and regulates the fate of their putative progeny in the Drosophila CNS. Development 122, 527–536 (1996).

  15. 15

    O'Keefe,D. D., Thor,S. & Thomas,J. B. Function and specificity of LIM domains in Drosophila nervous system and wing development. Development 125, 3915–3923 (1998).

  16. 16

    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).

  17. 17

    Lundgren,S. E., Callahan,C. A., Thor,S. & Thomas,J. B. Control of neuronal pathway selection by the Drosophila LIM homeodomain gene apterous . Development 121, 1769– 1773 (1995).

  18. 18

    Cheng,H.-J. & Flanagan,J. G. Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell 79, 157–168 (1994).

  19. 19

    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).

  20. 20

    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).

  21. 21

    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).

  22. 22

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

  23. 23

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

  24. 24

    Chan,S. S. et al. UNC-40, a C. elegans homolog of DCC (Deleted in Colorectal Cancer), is required in motile cells responding to UNC-6 netrin cues. Cell 87, 187–195 ( 1996).

  25. 25

    Seeger,M., Tear,G., Ferres,M. 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).

  26. 26

    Moreau-Fauvarque,C., Taillebourg,E., Boisoneau, E., Mesnard,J. & Dura,J. M. The receptor tyrosine kinase gene linotte is required for neuronal pathway selection in the Drosophila mushroom bodies. Mech. Dev. 78, 47– 61 (1998).

  27. 27

    Simon,A. F., Boquet,I., Synguelakis,M. & Preat,T. The Drosophila putative kinase linotte (derailed) prevents central brain axons from converging on a newly described interhemispheric ring. Mech. Dev. 76, 45–55 ( 1998).

  28. 28

    Hovens,C. M. et al. RYK, a receptor tyrosine kinase-related molecule with unusual kinase domain motifs. Proc. Natl Acad. Sci. USA 89, 11818–11822 (1992).

  29. 29

    Rubin,G. M. & Spradling,A. C. Genetic transformation of Drosophila with transposable element vectors. Science 218, 348–353 (1982).

  30. 30

    Callahan,C. A., Bonkovsky,J. L., Scully,A. L. & Thomas,J. B. derailed is required for muscle attachment site selection in Drosophila . Development 122, 2761– 2767 (1996).

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We thank T. Isshiki, G. Technau, C. Goodman, C. Klämbt and the Indiana Drosophila Stock Center for stocks, and G. Lemke and members of the Thomas lab for helpful comments. This work was supported by funds from the UC San Diego MSTP program to J.L.B., an HFSP Long-Term Fellowship to S.Y. and grants from the NIH to J.B.T.

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Correspondence to John B. Thomas.

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Bonkowsky, J., Yoshikawa, S., O'Keefe, D. et al. Axon routing across the midline controlled by the Drosophila Derailed receptor. Nature 402, 540–544 (1999) doi:10.1038/990122

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