Attraction versus repulsion: modular receptors make the difference in axon guidance.

Growth cones navigate along their pathways with remarkable speed and fidelity. Clearly a complex set of attractive and repulsive cues are present in the extracellular environment and are being interpreted by the growth cone. These papers demonstrate the critical role that receptors and receptor complexes play as effectors for these different guidance cues. As is often the case, while questions have been answered, new ones have been raised. Is growth cone guidance a continual battle between these different signals, or a balance between attraction and repulsion, as suggested by Bashaw and Goodman? Is the growth cone a democracy where the majority rules and every signal has an equal voice? Or have systems evolved that allow some signals to dominate at particular times, mechanisms that can switch a growth cone from an attractive to repulsive response rapidly, as is suggested by Hong and colleagues? Most likely, we will find that each of these scenarios is correct and that axon guidance in vivo utilizes both mechanisms.The next challenge will be to decipher what lies between the cytoplasmic domains of these axon guidance receptors and the cytoskeleton. What are the proteins that bind to these different cytoplasmic domains, and how are they regulated? Bashaw and Goodman point out that several families of repulsive guidance receptors have been identified and yet their cytoplasmic domains share no motifs in common. Does this suggest that these various classes of receptors will utilize distinct sig-naling pathways? Are there real differences between a Robo-mediated repulsive signal versus an UNC5-DCC repulsive signal? At some point all of these signaling pathways must converge on the proteins that directly regulate assembly and disassembly of the growth cone cytoskeleton. Unraveling how all of this is orchestrated will certainly be fascinating.Some initial insights are already being generated with the Xenopus axon turning assay. Using different pharmacological inhibitors, Poo, Tessier-Lavigne, and colleagues have identified signaling pathways that are required for axon turning to gradients of various attractants and repellents (11xMing, G.L, Song, H.J, Berninger, B, Holt, C.E, Tessier-Lavigne, M, and Poo, M.M. Neuron. 1997; 19: 1225–1235Abstract | Full Text | Full Text PDF | PubMed | Scopus (412)See all References, 12xMing, G.L, Song, H.J, Berninger, B, Inagaki, N, Tessier-Lavigne, M, and Poo, M.M. Neuron. 1999; 23: 139–148Abstract | Full Text | Full Text PDF | PubMed | Scopus (214)See all References, 13xSong, H.J, Ming, G.L, He, Z, Lehman, M, McKerracher, L, Tessier-Lavigne, M, and Poo, M.M. Science. 1998; 281: 1515–1518Crossref | PubMed | Scopus (661)See all References). Cyclic nucleotide signaling pathways (both cAMP and cGMP) have dramatic effects on attractive and repulsive turning responses to distinct guidance cues. Phospholipase C-γ, phosphoinoitide 3-kinase, and Ca2+ also can play critical roles. These in vitro studies have begun to identify common signaling pathways that are utilized by different classes of guidance cues. We are now poised to ask how these signaling pathways are linked with specific receptors in vivo during the complex process of axon guidance.§E-mail: seeger.9@osu.edu (M. A. S.), beattie.24@osu.edu (C. E. B.).