During embryonic development, axons travel considerable distances to reach their final targets in a stereotyped manner. The rapid advances in our understanding of this process have been aided by the use of invertebrate systems. Organisms such as Drosophila and C. elegans have been particularly useful owing to their relatively simple nervous systems and their susceptibility to rigorous genetic analysis.
A key strategy during axonal pathfinding is to break the distance to the target into a series of smaller trajectories between guidepost cells, the existence of which was discovered in the grasshopper limb bud. Netrin and its receptors are important mediators of the interaction between guidepost cells and axons, and genetic studies have aided in outlining the signalling cascade that mediates the action of netrin.
Roundabout (Robo) and Slit form part of a related signalling system that is crucial for axonal pathfinding. Their main role is to regulate the midline crossing of axons in the Drosophila nervous system, and a series of genetic studies have led to the definition of the intracellular cascade that might mediate their effect.
Pre-existing axons are important in guiding subsequent axon outgrowth, as follower axons often fasciculate with pioneers to reach their target area. It has been proposed that tracts have different molecular labels that subsequent axons can recognize. Various molecules, including neuroglian, N-cadherin and the fasciclins, have been identified that fulfil this labelling role.
Defasciculation is as important as fasciculation for pathfinding, and several additional molecules have been identified as being involved in this process. They include the semaphorins, Beaten path, Off-track and others. The intracellular routes whereby these molecules mediate defasciculation have begun to be charted.
Analysis of the Drosophila eye has led to the identification of additional guidance molecules that might not have been identified by the use of conventional phenotypic screens. Specifically, it has been useful for the identification of intracellular signalling elements that contribute to axon guidance.
Despite the identification of many molecules that underlie axon guidance, there might be others. For example, we know little about how axons integrate the simultaneous cues that they receive to generate a single response, and how they adapt their responses as they move along their pathway. Answers to these questions will require the combined use of the experimental advantages of both invertebrate and vertebrate systems.
Vertebrates and invertebrates share the formidable task of accurately establishing the elaborate connections that make up their nervous systems. Researchers investigating this process have the challenge of identifying the molecules and mechanisms that underlie this process. Each group of organisms offers their own advantages for piecing together the conserved constituents. Broadly speaking, the invertebrates have allowed the discovery of relevant genes through classical genetic screens for mutations that affect the process of axon guidance, whereas vertebrates provide numerous systems for the elaboration of the functional mechanisms. Here, we focus on the role of invertebrates in characterizing the molecular mechanisms of axon guidance.
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Tanaka, E. & Sabry, J. Making the connection: cytoskeletal rearrangements during growth cone guidance. Cell 83, 171–176 (1995).
Bentley, D. & O'Connor, T. P. Cytoskeletal events in growth cone steering. Curr. Opin. Neurobiol. 4, 43–48 (1994).
Suter, D. M. & Forscher, P. Substrate-cytoskeletal coupling as a mechanism for the regulation of growth cone motility and guidance. J. Neurobiol. 44, 97–113 (2000).
Wong, J. T., Yu, W. T. & O'Connor, T. P. Transmembrane grasshopper Semaphorin I promotes axon outgrowth in vivo. Development 124, 3597–607 (1997).
Dickson, B. Molecular mechanisms of axon guidance. Science 298, 1959–1964 (2002).
Fujita, S. C., Zipursky, S. L., Benzer, S., Ferrus, A. & Shotwell, S. L. Monoclonal antibodies against the Drosophila nervous system. Proc. Natl Acad. Sci. USA 79, 7929–7933 (1982). The first paper to identify markers that recognize individual neurons. This paper greatly aided the description of the neuronal architecture and enabled the accurate description of mutant phenotypes.
Zipursky, S. L., Venkatesh, T. R., Teplow, D. B. & Benzer, S. Neuronal development in the Drosophila retina: monoclonal antibodies as molecular probes. Cell 36, 15–26 (1984).
Tear, G. Neuronal guidance: a genetic perspective. Trends Genet. 15, 113–118 (1999).
Bastiani, M. J., Harrelson, A. L., Snow, P. M. & Goodman, C. S. Expression of fasciclin I and II glycoproteins on subsets of axon pathways during neuronal development in the grasshopper. Cell 48, 745–755 (1987).
Patel, N. H., Snow, P. M. & Goodman, C. S. Characterization and cloning of fasciclin III: a glycoprotein expressed on a subset of neurons and axon pathways in Drosophila. Cell 48, 975–988 (1987).
Bieber, A. J. et al. Drosophila neuroglian: a member of the immunoglobulin superfamily with extensive homology to the vertebrate neural adhesion molecule L1. Cell 59, 447–460 (1989).
Klambt, 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). An excellent descriptive paper that was the first to describe the biology of axon extension at the CNS midline and laid the basis for future work.
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). The first large scale histological screen for mutations that affect the development of CNS axon pathways in Drosophila . It led to the identification of commissureless and roundabout , among other genes.
Kolodziej, P. A., Jan, L. Y. & Jan, Y. N. Mutations that affect the length, fasciculation, or ventral orientation of specific sensory axons in the Drosophila embryo. Neuron 15, 273–286 (1995).
Hummel, T., Schimmelpfeng, K. & Klambt, C. Commissure formation in the embryonic CNS of Drosophila I. Identification of the required gene functions. Dev. Biol. 209, 381–398 (1999).
Hummel, T., Schimmelpfeng, K. & Klambt, C. Commissure formation in the embryonic CNS of Drosophila. II. Function of the different midline cells. Development 126, 771–779 (1999).
Salzberg, A. et al. Mutations affecting the pattern of the PNS in Drosophila reveal novel aspects of neuronal development. Neuron 13, 269–287 (1994).
Wightman, B., Baran, R. & Garriga, G. Genes that guide growth cones along the C. elegans ventral nerve cord. Development 124, 2571–2580 (1997).
Siddiqui, S. S. & Culotti, J. G. Examination of neurons in wild type and mutants of Caenorhabditis elegans using antibodies to horseradish peroxidase. J. Neurogenet. 7, 193–211 (1991).
McIntire, S. L., Garriga, G., White, J., Jacobson, D. & Horvitz, H. R. Genes necessary for directed axonal elongation or fasciculation in C. elegans. Neuron 8, 307–322 (1992). The first systematic screen for mutations that affect axon outgrowth.
Prokopenko, S. N., He, Y., Lu, Y. & Bellen, H. J. Mutations affecting the development of the peripheral nervous system in Drosophila: a molecular screen for novel proteins. Genetics 156, 1691–1715 (2000).
Huang, X., Cheng, H. J., Tessier-Lavigne, M. & Jin, Y. MAX-1, a novel PH/MyTH4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion. Neuron 34, 563–576 (2002).
Van Vactor, D., Sink, H., Fambrough, D., Tsoo, R. & Goodman, C. S. Genes that control neuromuscular specificity in Drosophila. Cell 73, 1137–1153 (1993). First genetic screen for mutations affecting neuromuscular connectivity in Drosophila . This screen led to the identification of Beaten path.
Martin, K. A. et al. Mutations disrupting neuronal connectivity in the Drosophila visual system. Neuron 14, 229–240 (1995).
Schmucker, D., Jackle, H. & Gaul, U. Genetic analysis of the larval optic nerve projection in Drosophila. Development 124, 937–948 (1997).
Rorth, P. et al. Systematic gain-of-function genetics in Drosophila. Development 125, 1049–1057 (1998). Application of a modular misexpression system of Drosophila to allow gain-of-function screens. The system involves the creation of modified P-elements containing GAL4 binding sequences (EP-elements) that can be mobilized to allow over- or misexpression of random genes in identified cells.
Kraut, R., Menon, K. & Zinn, K. A gain-of-function screen for genes controlling motor axon guidance and synaptogenesis in Drosophila. Curr. Biol. 11, 417–430 (2001).
Yoshikawa, S., McKinnon, R. D., Kokel, M. & Thomas, J. B. Wnt-mediated axon guidance via the Drosophila Derailed receptor. Nature 422, 583–588 (2003).
Merz, D. C. & Culotti, J. G. Genetic analysis of growth cone migrations in Caenorhabditis elegans. J. Neurobiol. 44, 281–288 (2000).
Newsome, T. P., Asling, B. & Dickson, B. J. Analysis of Drosophila photoreceptor axon guidance in eye-specific mosaics. Development 127, 851–860 (2000). Reports the generation of mosaic animals in a tissue-specific manner. This strategy was used here to perform a large-scale mutagenesis screen for mosaic larvae with visual system defects.
Lee, T. & Luo, L. Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis. Neuron 22, 451–461 (1999). Description of the MARCM (mosaic analysis with a repressible cell marker) system. This method takes mosaic analysis one step further by labelling only mutant cells within a normal background. Small numbers of neurons can be made homozygous mutant and uniquely labelled, allowing analysis in complicated tissues like the adult brain.
Myat, A. et al. Drosophila Nedd4, a ubiquitin ligase, is recruited by Commissureless to control cell surface levels of the roundabout receptor. Neuron 35, 447–459 (2002).
Keleman, K. et al. Comm sorts Robo to control axon guidance at the Drosophila midline. Cell 110, 415–427 (2002).
Schmucker, D. et al. Drosophila Dscam is an axon guidance receptor exhibiting extraordinary molecular diversity. Cell 101, 671–684 (2000).
Bate, M. Pioneer neurons in an insect embryo. Nature 260, 54–56 (1976). First description of pioneer neurons in an insect embryo and their use of guidepost cells. These pioneers provide a framework of pathways that are followed by later axons.
Bentley, D. & Caudy, M. Pioneer axons lose directed growth after selective killing of guidepost cells. Nature 304, 62–65 (1983). Demonstration that guidepost cells are involved in pioneer axon guidance. The authors show that selective destruction of guidepost cells affects pioneer axon trajectories in the grasshopper embryo.
Hobert, O. & Bulow, H. Development and maintenance of neuronal architecture at the ventral midline of C. elegans. Curr. Opin. Neurobiol. 13, 70–78 (2003).
White, J. G., Southgate, E., Thomson, J. N. & Brenner, S. The structure of the nervous system of the nematode Caenorhabditis elegans. Philos. Trans. R. Soc. Lond. B 314, 1–340 (1986).
Hedgecock, E. M., Culotti, J. G. & Hall, D. H. The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron 4, 61–85 (1990). First accurate description of mutations affecting axon guidance at the midline.
Chisholm, A. & Tessier-Lavigne, M. Conservation and divergence of axon guidance mechanisms. Curr. Opin. Neurobiol. 9, 603–615 (1999).
Wadsworth, W. G., Bhatt, H. & Hedgecock, E. M. Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron 16, 35–46 (1996).
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).
Keleman, K. & Dickson, B. J. Short- and long-range repulsion by the Drosophila Unc5 netrin receptor. Neuron 32, 605–617 (2001).
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).
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).
Hiramoto, M., Hiromi, Y., Giniger, E. & Hotta, Y. The Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution. Nature 406, 886–889 (2000).
Colavita, A. & Culotti, J. G. Suppressors of ectopic UNC-5 growth cone steering identify eight genes involved in axon guidance in Caenorhabditis elegans. Dev. Biol. 194, 72–85 (1998).
Gitai, Z., Yu, T. W., Lundquist, E. A., Tessier-Lavigne, M. & Bargmann, C. I. The netrin receptor UNC-40/DCC stimulates axon attraction and outgrowth through enabled and, in parallel, Rac and UNC-115/AbLIM. Neuron 37, 53–65 (2003).
Roof, D. J., Hayes, A., Adamian, M., Chishti, A. H. & Li, T. Molecular characterization of abLIM, a novel actin-binding and double zinc finger protein. J. Cell Biol. 138, 575–588 (1997).
Struckhoff, E. C. & Lundquist, E. A. The actin-binding protein UNC-115 is an effector of Rac signaling during axon pathfinding in C. elegans. Development 130, 693–704 (2003).
Gertler, F. B. et al. enabled, a dosage-sensitive suppressor of mutations in the Drosophila Abl tyrosine kinase, encodes an Abl substrate with SH3 domain-binding properties. Genes Dev. 9, 521–533 (1995).
Wills, Z., Marr, L., Zinn, K., Goodman, C. S. & Van Vactor, D. Profilin and the Abl tyrosine kinase are required for motor axon outgrowth in the Drosophila embryo. Neuron 22, 291–299 (1999).
Colavita, A., Krishna, S., Zheng, H., Padgett, R. W. & Culotti, J. G. Pioneer axon guidance by UNC-129, a C. elegans TGF-β. Science 281, 706–709 (1998).
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). Cloning and characterization of robo in Drosophila , a guidance receptor that defined a new subfamily of immunoglobulin superfamily proteins.
Kidd, T., Bland, K. S. & Goodman, C. S. Slit is the midline repellent for the robo receptor in Drosophila. Cell 96, 785–794 (1999).
Battye, R., Stevens, A. & Jacobs, J. R. Axon repulsion from the midline of the Drosophila CNS requires slit function. Development 126, 2475–2481 (1999).
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).
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).
Zallen, J. A., Yi, B. A. & Bargmann, C. I. The conserved immunoglobulin superfamily member SAX-3/Robo directs multiple aspects of axon guidance in C. elegans. Cell 92, 217–227 (1998).
Hao, J. C. et al. C. elegans slit acts in midline, dorsal-ventral, and anterior-posterior guidance via the SAX-3/Robo receptor. Neuron 32, 25–38 (2001).
Simpson, J. H., Kidd, T., Bland, K. S. & Goodman, C. S. Short-range and long-range guidance by slit and its Robo receptors. Robo and Robo2 play distinct roles in midline guidance. Neuron 28, 753–766 (2000).
Rajagopalan, S., Nicolas, E., Vivancos, V., Berger, J. & Dickson, B. J. Crossing the midline: roles and regulation of Robo receptors. Neuron 28, 767–777 (2000).
Schimmelpfeng, K., Gogel, S. & Klambt, C. The function of leak and kuzbanian during growth cone and cell migration. Mech. Dev. 106, 25–36 (2001).
Simpson, J. H., Bland, K. S., Fetter, R. D. & Goodman, C. S. 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).
Rajagopalan, S., Vivancos, V., Nicolas, E. & Dickson, B. J. Selecting a longitudinal pathway: Robo receptors specify the lateral position of axons in the Drosophila. Cell 103, 1033–1045 (2000). Molecular reinforcement of the labelled pathways model. References 64 and 65 show that Robo, Robo2 and Robo3 provide a combinatorial code that sets the sensitivity of an axon to the midline signal Slit, and therefore the distance the axon travels from the midline.
Zlatic, M., Landgraf, M. & Bate, M. Genetic specification of axonal arbors: atonal regulates robo3 to position terminal branches in the Drosophila nervous system. Neuron 37, 41–51 (2003).
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).
Kramer, S. G., Kidd, T., Simpson, J. H. & Goodman, C. S. Switching repulsion to attraction: changing responses to slit during transition in mesoderm migration. Science 292, 737–740 (2001).
Kinrade, E. F., Brates, T., Tear, G. & Hidalgo, A. Roundabout signalling, cell contact and trophic support confine longitudinal glia and axons in the Drosophila CNS. Development 128, 207–216 (2001).
Englund, C., Steneberg, P., Falileeva, L., Xylourgidis, N. & Samakovlis, C. Attractive and repulsive functions of Slit are mediated by different receptors in the Drosophila trachea. Development 129, 4941–4951 (2002).
Yu, T. W., Hao, J. C., Lim, W., Tessier-Lavigne, M. & Bargmann, C. I. Shared receptors in axon guidance: SAX-3/Robo signals via UNC-34/Enabled and a Netrin-independent UNC-40/DCC function. Nature Neurosci. 5, 1147–1154 (2002).
Bashaw, G. J., Kidd, T., Murray, D., Pawson, T. & Goodman, C. S. Repulsive axon guidance: Abelson and Enabled play opposing roles downstream of the roundabout receptor. Cell 101, 703–715 (2000).
Bashaw, G. J., Hu, H., Nobes, C. D. & Goodman, C. S. A novel Dbl family RhoGEF promotes Rho-dependent axon attraction to the central nervous system midline in Drosophila and overcomes Robo repulsion. J. Cell Biol. 155, 1117–1122 (2001).
Fritz, J. L. & VanBerkum, M. F. Regulation of rho family GTPases is required to prevent axons from crossing the midline. Dev. Biol. 252, 46–58 (2002).
Fritz, J. L. & VanBerkum, M. F. Calmodulin and son of sevenless dependent signaling pathways regulate midline crossing of axons in the Drosophila CNS. Development 127, 1991–2000 (2000).
Wills, Z. et al. A Drosophila homolog of cyclase-associated proteins collaborates with the Abl tyrosine kinase to control midline axon pathfinding. Neuron 36, 611–622 (2002).
Sun, Q., Bahri, S., Schmid, A., Chia, W. & Zinn, K. Receptor tyrosine phosphatases regulate axon guidance across the midline of the Drosophila embryo. Development 127, 801–812 (2000).
Stevens, A. & Jacobs, J. R. Integrins regulate responsiveness to slit repellent signals. J. Neurosci. 22, 4448–4455 (2002). This paper shows that the integrins have a genetic interaction with slit and suggests a role in the regulation of midline axon guidance signals in addition to their role in axon fasciculation.
Huang, X., Huang, P., Robinson, M. K., Stern, M. J. & Jin, Y. UNC-71, a disintegrin and metalloprotease (ADAM) protein, regulates motor axon guidance and sex myoblast migration in C. elegans. Development 130, 3147–3161 (2003).
Hoang, B. & Chiba, A. Genetic analysis on the role of integrin during axon guidance in Drosophila. J. Neurosci. 18, 7847–7855 (1998).
Bonkowsky, J. L., Yoshikawa, S., O'Keefe, D. D., Scully, A. L. & Thomas, J. B. Axon routing across the midline controlled by the Drosophila Derailed receptor. Nature 402, 540–544 (1999).
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).
Yoshikawa, S., Bonkowsky, J. L., Kokel, M., Shyn, S. & Thomas, J. B. The derailed guidance receptor does not require kinase activity in vivo. J. Neurosci. 21, RC119 (2001).
Charron, F., Stein, E., Jeong, J., McMahon, A. P. & Tessier-Lavigne, M. The morphogen sonic hedgehog is an axonal chemoattractant that collaborates with netrin-1 in midline axon guidance. Cell 113, 11–23 (2003).
Augsburger, A., Schuchardt, A., Hoskins, S., Dodd, J. & Butler, S. BMPs as mediators of roof plate repulsion of commissural neurons. Neuron 24, 127–141 (1999).
Butler, S. J. & Dodd, J. A role for BMP heterodimers in roof plate-mediated repulsion of commissural axons. Neuron 38, 389–401 (2003).
Whitington, P. M. Axon guidance factors in invertebrate development. Pharmacol. Ther. 58, 263–299 (1993).
Raper, J. A., Bastiani, M. & Goodman, C. S. Pathfinding by neuronal growthcones in grasshopper embryos. IV. The effects of ablating the A and Paxons upon the behaviour of the G growth cone. J. Neurosci. 4, 2329–2345 (1984).
Hidalgo, A. & Brand, A. H. Targeted neuronal ablation: the role of pioneer neurons in guidance and fasciculation in the CNS of Drosophila. Development 124, 3253–3262 (1997).
du Lac, S., Bastiani, M. J. & Goodman, C. S. Guidance of neuronal growth cones in the grasshopper embryo. II. Recognition of a specific axonal pathway by the aCC neuron. J. Neurosci. 6, 3532–3541 (1986).
Bastiani, M. J., du Lac, S. & Goodman, C. S. Guidance of neuronal growth cones in the grasshopper embryo. I. Recognition of a specific axonal pathway by the pCC neuron. J. Neurosci. 6, 3518–3531 (1986).
Goodman, C. S. et al. Cell recognition during neuronal development. Science 225, 1271–1279 (1984).
Raper, J. A., Bastiani, M. & Goodman, C. S. Pathfinding by neuronal growthcones in grasshopper embryos. II. Selective fasciculation onto specific axonal pathways. J. Neurosci. 3, 31–41 (1983). In this paper, it is proposed that growth cones of later differentiating neurons are programmed to choose between and elongate on the axons of specifically labelled pioneer axons, leading to the labelled pathway hypothesis.
Grenningloh, G. & Goodman, C. S. Pathway recognition by neuronal growth cones: genetic analysis of neural cell adhesion molecules in Drosophila. Curr. Opin. Neurobiol. 2, 42–47 (1992).
Grenningloh, G. et al. Molecular genetics of neuronal recognition in Drosophila: evolution and function of immunoglobulin superfamily cell adhesion molecules. Cold Spring Harb. Symp. Quant. Biol. 55, 327–340 (1990).
Dubreuil, R. R. et al. Neuroglian-mediated cell adhesion induces assembly of the membrane skeleton at cell contact sites. J. Cell Biol. 133, 647–655 (1996).
Elkins, T., Hortsch, M., Bieber, A. J., Snow, P. M. & Goodman, C. S. Drosophila fasciclin I is a novel homophilic adhesion molecule that along with fasciclin III can mediate cell sorting. J. Cell Biol. 110, 1825–1832 (1990).
Snow, P. M., Bieber, A. J. & Goodman, C. S. Fasciclin III: a novel homophilic adhesion molecule in Drosophila. Cell 59, 313–323 (1989).
Elkins, T., Zinn, K., McAllister, L., Hoffmann, F. M. & Goodman, C. S. Genetic analysis of a Drosophila neural cell adhesion molecule: interaction of fasciclin I and Abelson tyrosine kinase mutations. Cell 60, 565–575 (1990). The first paper to show that there genetic redundancy or compensatory mechanisms can maintain normal axon outgrowth.
Speicher, S. et al. Neurotactin functions in concert with other identified CAMs in growth cone guidance in Drosophila. Neuron 20, 221–233 (1998).
Lin, D. M., Fetter, R. D., Kopczynscki, C., Grenningloh, G. & Goodman, C. S. Genetic analysis of fasciclin II in Drosophila: defasciculation, refasciculation, and altered fasciculation. Neuron 13, 1055–1069 (1994).
Iwai, Y. et al. Axon patterning requires DN-cadherin a novel neuronal adhesion receptor, in the Drosophila embryonic CNS. Neuron 19, 77–89 (1997).
Broadbent, I. D. & Pettitt, J. The C. elegans hmr-1 gene can encode a neuronal classic cadherin involved in the regulation of axon fasciculation. Curr. Biol. 12, 59–63 (2002).
Garcia-Alonso, L., Fetter, R. D. & Goodman, C. S. Genetic analysis of Laminin A in Drosophila: extracellular matrix containing laminin A is required for ocellar axon pathfinding. Development 122, 2611–2621 (1996).
Forrester, W. C. & Garriga, G. Genes necessary for C. elegans cell and growth cone migrations. Development 124, 1831–1843 (1997).
Goodhill, G. J. A theoretical model of axon guidance by the Robo code. Neural Comput. 15, 549–564 (2003).
Rhee, J. et al. Activation of the repulsive receptor Roundabout inhibits N-cadherin-mediated cell adhesion. Nature Cell Biol. 4, 798–805 (2002). Evidence for a biochemical inhibition of N-cadherin signalling by the guidance receptor Robo. Activation of Robo results in the formation of a receptor complex between Robo and N-cadherin, uncoupling N-cadherin from its association with the cytoskeleton.
Emerson, M. M. & Van Vactor, D. Robo is Abl to block N-Cadherin function. Nature Cell Biol. 4, E227–E230 (2002).
Hidalgo, A. & Booth, G. E. Glia dictate pioneer axon trajectories in the Drosophila embryonic CNS. Development 127, 393–402 (2000).
Hidalgo, A., Urban, J. & Brand, A. H. Targeted ablation of glia disrupts axon tract formation in the Drosophila CNS. Development 121, 3703–3712 (1995).
Tang, J., Landmesser, L. & Rutishauser, U. Polysialic acid influences specific pathfinding by avian motoneurons. Neuron 8, 1031–1044 (1992).
Lin, D. M. & Goodman, C. S. Ectopic and increased expression of Fasciclin II alters motorneuron growth cone guidance. Neuron 13, 507–523 (1994).
Mushegian, A. R. The Drosophila Beat protein is related to adhesion proteins that contain immunoglobulin domains. Curr. Biol. 7, R336–8 (1997).
Pipes, G. C., Lin, Q., Riley, S. E. & Goodman, C. S. The Beat generation: a multigene family encoding IgSF proteins related to the Beat axon guidance molecule in Drosophila. Development 128, 4545–4552 (2001).
Fambrough, D. & Goodman, C. S. The Drosophila beaten path gene encodes a novel secreted protein that regulates defasciculation at motor axon choice points. Cell 87, 1049–1058 (1996).
Pasterkamp, R. J. & Kolodkin, A. L. Semaphorin junction: making tracks toward neural connectivity. Curr. Opin. Neurobiol. 13, 79–89 (2003).
Yu, H. H., Araj, H. H., Ralls, S. A. & Kolodkin, A. L. The transmembrane Semaphorin SemaI is required in Drosophila for embryonic motor axon and CNS axon guidance. Neuron 20, 207–220 (1998).
Winberg, M. L. et al. Plexin A is a neuronal semaphorin receptor that controls axon guidance. Cell 95, 903–916 (1998).
Yu, H. H., Huang, A. S. & Kolodkin, A. L. Semaphorin-1a acts in concert with the cell adhesion molecules fasciclin II and connectin to regulate axon fasciculation in Drosophila. Genetics 156, 723–731 (2000).
Isbister, C. M., Tsai, A., Wong, S. T., Kolodkin, A. L. & O'Connor, T. P. Discrete roles for secreted and transmembrane semaphorins in neuronal growth cone guidance in vivo. Development 126, 2007–2019 (1999).
Winberg, M. L. et al. The transmembrane protein Off-track associates with Plexins and functions downstream of Semaphorin signaling during axon guidance. Neuron 32, 53–62 (2001).
Terman, J. R., Mao, T., Pasterkamp, R. J., Yu, H. H. & Kolodkin, A. L. MICALs, a family of conserved flavoprotein oxidoreductases, function in plexin-mediated axonal repulsion. Cell 109, 887–900 (2002). This paper shows that Drosophila Mical, a large multidomain protein that is expressed in axons, interacts with the neuronal PlexA receptor and is required for Sema1a–PlexA-mediated repulsive axon guidance. Mical has a flavoprotein monooxygenase domain, indicating that oxidoreductases might have a role in repulsive axon guidance.
Hu, H., Marton, T. F. & Goodman, C. S. Plexin B mediates axon guidance in Drosophila by simultaneously inhibiting active Rac and enhancing RhoA signaling. Neuron 32, 39–51 (2001).
Streuli, M., Krueger, N. X., Tsai, A. Y. & Saito, H. A family of receptor-linked protein tyrosine phosphatases in humans and Drosophila. Proc. Natl Acad. Sci. USA 86, 8698–8702 (1989).
Tian, S. S., Tsoulfas, P. & Zinn, K. Three receptor-linked protein-tyrosine phosphatases are selectively expressed on central nervous system axons in the Drosophila embryo. Cell 67, 675–680 (1991).
Krueger, N. X. et al. The transmembrane tyrosine phosphatase DLAR controls motor axon guidance in Drosophila. Cell 84, 611–622 (1996).
Sun, Q., Schindelholz, B., Knirr, M., Schmid, A. & Zinn, K. Complex genetic interactions among four receptor tyrosine phosphatases regulate axon guidance in Drosophila. Mol. Cell. Neurosci. 17, 274–291 (2001).
Desai, C. J., Krueger, N. X., Saito, H. & Zinn, K. Competition and cooperation among receptor tyrosine phosphatases control motoneuron growth cone guidance in Drosophila. Development 124, 1941–1952 (1997).
Schindelholz, B., Knirr, M., Warrior, R. & Zinn, K. Regulation of CNS and motor axon guidance in Drosophila by the receptor tyrosine phosphatase DPTP52F. Development 128, 4371–4382 (2001).
Kaufmann, N., Wills, Z. P. & Van Vactor, D . Drosophila Rac1 controls motor axon guidance. Development 125, 453–461 (1998).
Bateman, J., Shu, H. & Van Vactor, D. The guanine nucleotide exchange factor trio mediates axonal development in the Drosophila embryo. Neuron 26, 93–106 (2000).
Wills, Z., Bateman, J., Korey, C. A., Comer, A. & Van Vactor, D. The tyrosine kinase Abl and its substrate enabled collaborate with the receptor phosphatase DLar to control motor axon guidance. Neuron 22, 301–312 (1999).
Steven, R. et al. UNC-73 activates the Rac GTPase and is required for cell and growth cone migrations in C. elegans. Cell 92, 785–795 (1998).
Sink, H., Rehm, E. J., Richstone, L., Bulls, Y. M. & Goodman, C. S. sidestep encodes a target-derived attractant essential for motor axon guidance in Drosophila. Cell 105, 57–67 (2001).
Winberg, M. L., Mitchell, K. J. & Goodman, C. S. Genetic analysis of the mechanisms controlling target selection: complementary and combinatorial functions of netrins, semaphorins and IgCAMs. Cell 93, 581–591 (1998).
Davis, G. W., Schuster, C. M. & Goodman, C. S. Genetic analysis of the mechanisms controlling target selection: target-derived Fasciclin II regulates the pattern of synapse formation. Neuron 19, 561–573 (1997).
Younossi-Hartenstein, A. & Hartenstein, V. The role of the trachea and musculature during pathfinding of Drosophila embryonic sensory axons. Dev. Biol. 158, 430–447 (1993).
Giniger, E., Jan, L. Y. & Jan, Y. N. Specifying the path of the intersegmental nerve of the Drosophila embryo: a role for Delta and Notch. Development 117, 431–440 (1993).
Crowner, D., Le Gall, M., Gates, M. A. & Giniger, E. Notch steers Drosophila ISNb motor axons by regulating the Abl signaling pathway. Curr. Biol. 13, 967–972 (2003).
Garrity, P. A. et al. Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein. Cell 85, 639–650 (1996).
Lee, C. H., Herman, T., Clandinin, T. R., Lee, R. & Zipursky, S. L. N-cadherin regulates target specificity in the Drosophila visual system. Neuron 30, 437–450 (2001).
Newsome, T. P. et al. Trio combines with dock to regulate Pak activity during photoreceptor axon pathfinding in Drosophila. Cell 101, 283–294 (2000).
Hing, H., Xiao, J., Harden, N., Lim, L. & Zipursky, S. L. Pak functions downstream of Dock to regulate photoreceptor axon guidance in Drosophila. Cell 97, 853–863 (1999).
Liebl, E. C. et al. Dosage-sensitive, reciprocal genetic interactions between the Abl tyrosine kinase and the putative GEF trio reveal trio's role in axon pathfinding. Neuron 26, 107–118 (2000).
Awasaki, T. et al. The Drosophila trio plays an essential role in patterning of axons by regulating their directional extension. Neuron 26, 119–131 (2000).
Ang, L. H., Kim, J., Stepensky, V. & Hing, H. Dock and Pak regulate olfactory axon pathfinding in Drosophila. Development 130, 1307–1316 (2003).
Song, J., Wu, L., Chen, Z., Kohanski, R. A. & Pick, L. Axons guided by insulin receptor in Drosophila visual system. Science 300, 502–505 (2003).
Rao, Y., Pang, P., Ruan, W., Gunning, D. & Zipursky, S. L. brakeless is required for photoreceptor growth-cone targeting in Drosophila. Proc. Natl Acad. Sci. USA 97, 5966–5971 (2000).
Senti, K., Keleman, K., Eisenhaber, F. & Dickson, B. J. brakeless is required for lamina targeting of R1–R6 axons in the Drosophila visual system. Development 127, 2291–2301 (2000).
Kaminker, J. S., Canon, J., Salecker, I. & Banerjee, U. Control of photoreceptor axon target choice by transcriptional repression of Runt. Nature Neurosci. 5, 746–750 (2002).
Poeck, B., Fischer, S., Gunning, D., Zipursky, S. L. & Salecker, I. Glial cells mediate target layer selection of retinal axons in the developing visual system of Drosophila. Neuron 29, 99–113 (2001).
Suh, G. S. et al. Drosophila JAB1/CSN5 acts in photoreceptor cells to induce glial cells. Neuron 33, 35–46 (2002).
Gong, Q., Rangarajan, R., Seeger, M. & Gaul, U. The netrin receptor frazzled is required in the target for establishment of retinal projections in the Drosophila visual system. Development 126, 1451–1456 (1999).
Thomas, R. C. et al. Drosophila LAR regulates R1–R6 and R7 target specificity in the visual system. Neuron 32, 237–248 (2001).
Maurel-Zaffran, C., Suzuki, T., Gahmon, G., Treisman, J. E. & Dickson, B. J. Cell-autonomous and-nonautonomous functions of LAR in R7 photoreceptor axon targeting. Neuron 25, 225–235 (2001).
Garrity, P. A. et al. Retinal axon target selection in Drosophila is regulated by a receptor protein tyrosine phosphatase. Neuron 22, 707–717 (1999).
Lee, R. C. et al. The protocadherin Flamingo is required for axon target selection in the Drosophila visual system. Nature Neurosci. 6, 557–563 (2003).
Senti, K.-A. et al. Flamingo regulates R8 axon–axon and axon–target interactions in the Drosophila visual system. Curr. Biol. 13, 828–832 (2003).
Chae, J. et al. The Drosophila tissue polarity gene starry night encodes a member of the protocadherin family. Development 126, 5421–5429 (1999).
Lu, B., Usui, T., Uemura, T., Jan, L. Y. & Jan, Y. N. Flamingo controls the planar polarity of sensory bristles and asymmetric division of sensory organ precursors in Drosophila. Curr. Biol. 9, 1247–1250 (1999).
Gao, F.-B., Kohwi, M., Brenman, J. E., Jan, L. Y. & Jan, Y. N. Control of dendritic field formation in Drosophila: the roles of Flamingo and Competition between homologous neurons. Neuron 28, 91–101 (2000).
Condron, B. Gene expression is required for correct axon guidance. Curr. Biol. 12, 1665–1669 (2002).
We thank A. Hidalgo and D. van Vactor for permission to use previously published images. We also acknowledge financial support from the BBSRC (S.A. & G.T.) and the MRC (G.T.).
- ENHANCER AND SUPPRESSOR SCREENS
Systems that are used to identify genes that exacerbate or reduce the phenotype caused by mutations in other genes.
- CLONAL MARKER
A marker that allows the identification of the progeny derived from a single cell (a clone).
Tissue containing two or more genetically distinct cell types.
A homotrimeric glycoprotein found in platelets, and in the extracellular matrix of endothelial cells and fibroblasts. It is involved in platelet aggregation.
- SH DOMAINS
Src-homology domains are involved in interactions with phosphorylated tyrosine residues on other proteins (SH2 domains) or with proline-rich sections of other proteins (SH3 domains).
- FLAVOPROTEIN MONOOXYGENASES
A subclass of proteins that are involved in the catalysis of redox reactions and use flavin-adenine dinucleotide as a coenzyme.
Two neurogenic genes originally described in Drosophila, the products of which interact directly. Notch and Delta are now known to have several functions, but were first identified as being necessary to prevent ectodermal cells from becoming neuroblasts.
- ALTERNATIVE SPLICING
During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.
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Araújo, S., Tear, G. Axon guidance mechanisms and molecules: lessons from invertebrates. Nat Rev Neurosci 4, 910–922 (2003). https://doi.org/10.1038/nrn1243
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