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Gene Review

robo  -  roundabout

Drosophila melanogaster

Synonyms: BEST:GM07780, CG13521, CT32892, D-Robo1, Dmel\CG13521, ...
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High impact information on robo

  • Axon growth across the Drosophila midline requires Comm to downregulate Robo, the receptor for the midline repellent Slit [1].
  • Previous studies suggested that Roundabout (Robo) is a repulsive guidance receptor on growth cones that binds to an unknown midline ligand [2].
  • Taking commissural axons in the vertebrate spinal cord and the Drosophila ventral nerve cord as examples, we examine how commissural axon pathfinding is regulated by the Slit family of guidance cues and their Robo family receptors [3].
  • Slit is secreted by cells at the midline of the central nervous system, where it binds to Roundabout (Robo) receptors and functions as a potent repellent [4].
  • Mesoderm cells expressing Robo receptors initially migrate away from Slit at the midline [4].

Biological context of robo

  • The absence of suppression causes the robo phenotype: longitudinal axons project toward the midline, as if running around a roundabout (rotary) [5].
  • In the guidance of neuronal growth cones in Drosophila, there is a phenotypic interaction between slit and robo heterozygotes, and also with genes required for Robo signaling [6].
  • Lateral positioning at the dorsal midline: Slit and Roundabout receptors guide Drosophila heart cell migration [7].
  • Here, we report a novel role of the Drosophila slit, robo, and robo2 genes in heart morphogenesis [8].
  • We examine the function of these proteins in the visual system by isolating a novel allele of slit that preferentially disrupts visual system expression of Slit and by creating transgenic RNA interference flies to inhibit the function of each Drosophila Robo in a tissue-specific fashion [9].

Anatomical context of robo

  • Mutations in robo lead to the opposite misrouting, such that some growth cones that normally extend only on their own side instead now project across the midline [10].
  • Heparan sulfate proteoglycan syndecan promotes axonal and myotube guidance by slit/robo signaling [11].
  • In robo(-/-), slit(-/-), and robo(-/+) slit(-/+) mutants, lateral cluster sensory neurons misproject to cells and axons in the nearby ventral' (v') cluster [12].
  • These results suggest a novel, non-cell-autonomous mechanism for axon guidance by robo family genes: Robo2 expressed on the trachea acts as an attractant for the dorsal sensory growth cones [12].
  • In robo mutants, medial filopodia can remain extended for longer periods and can develop into contralateral branches [13].

Associations of robo with chemical compounds

  • Our results are not consistent with the proposal based on genetic analysis in Drosophila that the sole function of Slit and Robo during midline guidance is to repress Netrin attraction [14].
  • Binding site for Robo receptors revealed by dissection of the leucine-rich repeat region of Slit [15].
  • Mutation of conserved basic residues in IG1 (Lys-69, Arg-117, Lys-122, Lys-123), but not in IG2, reduced binding of Robo IG1-5 to heparin, in full agreement with the Robo-heparin co-crystal structure [16].

Physical interactions of robo

  • We report here the isolation of vertebrate homologs of the Drosophila slit gene and show that Slit protein binds to the transmembrane protein Roundabout (Robo) [17].
  • Vilse and its human homolog bind directly to the intracellular domains of the corresponding Robo receptors and promote the hydrolysis of RacGTP and, less efficiently, of Cdc42GTP [18].

Regulatory relationships of robo

  • Robo repulsion is downregulated by the Commissureless (Comm) protein, allowing axons to cross the midline [19].
  • Here we show that a combinatorial code of Robo receptors controls lateral position in the CNS by responding to this presumptive Slit gradient [20].
  • We show that, before reaching the segmental boundary, the longitudinal axons' responsiveness to Netrin presented on the commissure is suppressed by Roundabout (ROBO), through counteracting Gq signaling [5].
  • Heterozygous loss of Roundabout enhances the ctDrac phenotype and causes errors in embryos expressing dnRho or ctRho [21].

Other interactions of robo

  • Overexpression of comm is also dosage-sensitive and leads to a phenotype identical to robo loss-of-function [22].
  • Groups of sensory neurons possess distinct blends of Robo and Robo3 and disruption of levels by loss-of-function or ectopic expression results in aberrant targeting [23].
  • The results suggest that beta-Spectrin contributes to midline repulsion through the regulation of Slit-Robo pathway components [24].
  • Further support for this model is provided by genetic interactions that both capt and Abl display with multiple members of the Roundabout receptor family [25].
  • These studies identify Capulet as part of an emerging pathway linking guidance signals to regulation of cytoskeletal dynamics and suggest that the Abl pathway mediates signals downstream of multiple Roundabout receptors [25].

Analytical, diagnostic and therapeutic context of robo


  1. Comm sorts robo to control axon guidance at the Drosophila midline. Keleman, K., Rajagopalan, S., Cleppien, D., Teis, D., Paiha, K., Huber, L.A., Technau, G.M., Dickson, B.J. Cell (2002) [Pubmed]
  2. Slit is the midline repellent for the robo receptor in Drosophila. Kidd, T., Bland, K.S., Goodman, C.S. Cell (1999) [Pubmed]
  3. Regulation of commissural axon pathfinding by slit and its robo receptors. Dickson, B.J., Gilestro, G.F. Annu. Rev. Cell Dev. Biol. (2006) [Pubmed]
  4. Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration. Kramer, S.G., Kidd, T., Simpson, J.H., Goodman, C.S. Science (2001) [Pubmed]
  5. ROBO directs axon crossing of segmental boundaries by suppressing responsiveness to relocalized Netrin. Hiramoto, M., Hiromi, Y. Nat. Neurosci. (2006) [Pubmed]
  6. Slit coordinates cardiac morphogenesis in Drosophila. Macmullin, A., Jacobs, J.R. Dev. Biol. (2006) [Pubmed]
  7. Lateral positioning at the dorsal midline: Slit and Roundabout receptors guide Drosophila heart cell migration. Santiago-Martínez, E., Soplop, N.H., Kramer, S.G. Proc. Natl. Acad. Sci. U.S.A. (2006) [Pubmed]
  8. Slit and Robo control cardiac cell polarity and morphogenesis. Qian, L., Liu, J., Bodmer, R. Curr. Biol. (2005) [Pubmed]
  9. Compartmentalization of visual centers in the Drosophila brain requires Slit and Robo proteins. Tayler, T.D., Robichaux, M.B., Garrity, P.A. Development (2004) [Pubmed]
  10. Mutations affecting growth cone guidance in Drosophila: genes necessary for guidance toward or away from the midline. Seeger, M., Tear, G., Ferres-Marco, D., Goodman, C.S. Neuron (1993) [Pubmed]
  11. Heparan sulfate proteoglycan syndecan promotes axonal and myotube guidance by slit/robo signaling. Steigemann, P., Molitor, A., Fellert, S., Jäckle, H., Vorbrüggen, G. Curr. Biol. (2004) [Pubmed]
  12. Roundabout gene family functions during sensory axon guidance in the drosophila embryo are mediated by both Slit-dependent and Slit-independent mechanisms. Parsons, L., Harris, K.L., Turner, K., Whitington, P.M. Dev. Biol. (2003) [Pubmed]
  13. Effects of roundabout on growth cone dynamics, filopodial length, and growth cone morphology at the midline and throughout the neuropile. Murray, M.J., Whitington, P.M. J. Neurosci. (1999) [Pubmed]
  14. Independent functions of Slit-Robo repulsion and Netrin-Frazzled attraction regulate axon crossing at the midline in Drosophila. Garbe, D.S., Bashaw, G.J. J. Neurosci. (2007) [Pubmed]
  15. Binding site for Robo receptors revealed by dissection of the leucine-rich repeat region of Slit. Howitt, J.A., Clout, N.J., Hohenester, E. EMBO J. (2004) [Pubmed]
  16. Structural and functional analysis of slit and heparin binding to immunoglobulin-like domains 1 and 2 of Drosophila Robo. Fukuhara, N., Howitt, J.A., Hussain, S.A., Hohenester, E. J. Biol. Chem. (2008) [Pubmed]
  17. Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Li, H.S., Chen, J.H., Wu, W., Fagaly, T., Zhou, L., Yuan, W., Dupuis, S., Jiang, Z.H., Nash, W., Gick, C., Ornitz, D.M., Wu, J.Y., Rao, Y. Cell (1999) [Pubmed]
  18. Vilse, a conserved Rac/Cdc42 GAP mediating Robo repulsion in tracheal cells and axons. Lundström, A., Gallio, M., Englund, C., Steneberg, P., Hemphälä, J., Aspenström, P., Keleman, K., Falileeva, L., Dickson, B.J., Samakovlis, C. Genes Dev. (2004) [Pubmed]
  19. Receptor tyrosine phosphatases regulate axon guidance across the midline of the Drosophila embryo. Sun, Q., Bahri, S., Schmid, A., Chia, W., Zinn, K. Development (2000) [Pubmed]
  20. Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position. Simpson, J.H., Bland, K.S., Fetter, R.D., Goodman, C.S. Cell (2000) [Pubmed]
  21. Regulation of rho family GTPases is required to prevent axons from crossing the midline. Fritz, J.L., VanBerkum, M.F. Dev. Biol. (2002) [Pubmed]
  22. Dosage-sensitive and complementary functions of roundabout and commissureless control axon crossing of the CNS midline. Kidd, T., Russell, C., Goodman, C.S., Tear, G. Neuron (1998) [Pubmed]
  23. Positioning sensory terminals in the olfactory lobe of Drosophila by Robo signaling. Jhaveri, D., Saharan, S., Sen, A., Rodrigues, V. Development (2004) [Pubmed]
  24. {beta}-Spectrin functions independently of Ankyrin to regulate the establishment and maintenance of axon connections in the Drosophila embryonic CNS. Garbe, D.S., Das, A., Dubreuil, R.R., Bashaw, G.J. Development (2007) [Pubmed]
  25. A Drosophila homolog of cyclase-associated proteins collaborates with the Abl tyrosine kinase to control midline axon pathfinding. Wills, Z., Emerson, M., Rusch, J., Bikoff, J., Baum, B., Perrimon, N., Van Vactor, D. Neuron (2002) [Pubmed]
  26. The mouse SLIT family: secreted ligands for ROBO expressed in patterns that suggest a role in morphogenesis and axon guidance. Yuan, W., Zhou, L., Chen, J.H., Wu, J.Y., Rao, Y., Ornitz, D.M. Dev. Biol. (1999) [Pubmed]
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