The middle and the end: slit brings guidance and branching together in axon pathway selection.

The multitalented nature of Slit raises interesting questions about the mechanisms downstream. Do Robo1 and Robo2 have similar or different functions? Are all the actions of Slits mediated by Robo family receptors? More generally, bifunctionality is now a common theme among axon guidance cues, though we still understand little about the mechanisms that translate signals at the cell surface into differential responses within the cell. Studies in vitro show that intracellular cyclic nucleotide levels can interconvert responses between attraction and repulsion, implying that these opposite types of guidance share a common signaling machinery (Song et al. 1997xSong, H., Ming, G., and Poo, M.-M. Nature. 1997; 388: 275–279Crossref | PubMed | Scopus (461)See all ReferencesSong et al. 1997). The identification of neurotrophins and Slit proteins as molecules that can control guidance, and can also promote prominent collateral branches, suggests a common machinery for guidance and branching too. Intriguingly, careful in vitro observations have indicated that sprouts, which might be precursors to collateral branches, can form in response to collapse of the primary growth cone (Davenport et al. 1999xDavenport, R.W., Thies, E., and Cohen, M.L. Nat. Neurosci. 1999; 2: 254–259Crossref | PubMed | Scopus (55)See all ReferencesDavenport et al. 1999), or at axonal positions that have been previously marked by growth cone arrest (Szebenyi et al. 1998xSzebenyi, G., Callaway, J.L., Dent, E.W., and Kalil, K. J. Neurosci. 1998; 18: 7930–7940PubMedSee all ReferencesSzebenyi et al. 1998). These studies suggest potential mechanisms for a direct link between the middle and the end, though it is not yet known whether this may be relevant to sprouting in vivo (e.g., Ozaki and Snider 1997xOzaki, S. and Snider, W.D. J. Comp. Neurol. 1997; 380: 215–229Crossref | PubMed | Scopus (120)See all ReferencesOzaki and Snider 1997). It will also be interesting to know whether the machinery that regulates the middle and the end also controls the beginning—the initial polarity of axon outgrowth.These new studies in axon pathway selection may also provide a glimpse of another kind of beginning. Up to now, research on axon guidance molecules has been in the realm of basic science, but one can increasingly begin to see the potential for clinical applications. Wang and colleagues point out that target-derived branch promoting factors might prove useful in the regeneration of connections after spinal injury (Wang et al. 1999xWang, K.H., Brose, K., Arnott, D., Kidd, T., Goodman, C.S., Henzel, C., and Tessier-Lavigne, M. Cell. 1999; 96: 771–784Abstract | Full Text | Full Text PDF | PubMedSee all ReferencesWang et al. 1999). Another example is tactile allodynia, where nerve injury or inflammation can induce collateral sprouting of mechanoreceptor axons within the spinal cord, switching the perception of innocuous stimuli to that of painful ones (Woolf 1997xWoolf, C.J. Prog. Pain Res. Mgmt. 1997; 9: 171–200See all ReferencesWoolf 1997). Here, there might be a clinical use for branch inhibition. Eventually, Slit proteins or other factors that can modulate axon branching or guidance might find applications in many conditions where the outcome could be improved by the regulation of neural plasticity.*E-mail: davie@hms.harvard.edu and flanagan@hms.harvard.edu.