Oh, for some simple guidance

Abstract

Although I don't feel very old, I must say that things certainly seemed simpler when I was younger: take axon guidance, for example. It had long been proposed that axons were guided by signals secreted from target tissues. By assaying for axon-attracting activities, several candidate signalling molecules were isolated, of which the most well known are probably the vertebrate Netrins and their Drosophila (Netrin-A/B) and Caenorhabditis elegans (Unc-6) orthologues. It was hypothesized that Netrin-1 protein, secreted from the ventral region of the developing vertebrate neural tube, establishes a gradient of attracting activity that directs the ventral migration of the axons of dorsally located neurons. Consistent with this idea, mutations in the mouse netrin 1 gene disrupt the ventral migration of these neurons and mutations in a candidate Netrin receptor, deleted in colorectal cancer (DCC), which is expressed on the migrating axons, producing a similar axon guidance phenotype. Recent reports, however, suggest that Netrin signalling might not be as straightforward as previously thought.Genetic evidence from Drosophila indicates that the activity of the ADAM metalloprotease, Kuzbanian, is required for correct axon guidance. Galko and Tessier-Levigne1xFunction of an axonal chemoattractant modulated by metalloprotease activity. Galko, M.J. and Tessier-Levigne, M. Science. 2000; 289: 1365–1367Crossref | PubMed | Scopus (136)See all References provide support for this in the vertebrate system by demonstrating that a previously identified netrin-synergizing activity (NSA) bears all the hallmarks of being a metalloprotease; NSA can be faithfully mimicked by IC-3, a specific inhibitor of metalloprotease activity. Moreover, they show that the netrin receptor DCC is a metalloprotease substrate, cleavage of which is efficiently blocked by IC-3.In another paper, Hiramoto et al.2xThe Drosophila Netrin receptor Frazzled guides axons by controlling Netrin distribution. Hiramoto, M. et al. Nature. 2000; 406: 886–889Crossref | PubMed | Scopus (89)See all References report that the product of the Drosophila frazzled gene, the fly orthologue of Netrin receptor DCC, is not uniformly distributed in the membrane of expressing cells and that this distribution is controlled by the cytoplasmic domain of the protein. Perhaps more surprisingly, the authors show that Frazzled is not required in the neurons whose migration is disrupted in frazzled mutants. Through a series of elegant misexpression experiments, the authors provide evidence that Frazzled does indeed bind Drosophila Netrins, but rather than transducing a signal, as would a canonical receptor, Frazzled presents the bound Netrin to other receptors. As DCC has been shown to bind Netrin, the authors suggest that a similar process might take place during guidance of axons in vertebrates.Thus, the control of axon guidance by Netrin/DCC/Frazzled is not just a matter of target tissues secreting signals that are recognised and transduced by receptors in the migrating neurons. It appears more likely that a fine balance is struck between the availability of active and proteolytically inactivated DCC/Frazzled and that the precise subcellular localization of these proteins controls the ability of receptor–Netrin complexes to be recognised by a second class of currently unidentified receptors on the migrating axonal growth cones. Not such a simple story after all.