Semaphorin Signaling A Little Less Per-Plexin

Recent advances in our understanding of axon guidance during neural development are highlighted by the characterization of several gene families containing members capable of functioning as repellents. These include ephrins, netrins, and semaphorins. Though future work will undoubtedly result in the identification of still more repellents, the wealth of information now in hand concerning the cellular and molecular basis of repulsive guidance demands that we turn our attention toward how these repulsive cues actually direct discrete steering events. Pharmacological experiments are beginning to provide important insights into the basis of repulsive guidance signaling mechanisms in cell culture (Song et al., 1998). However, the characterization of endogenous receptors through which these cues transduce extracel-lular signals is paramount to addressing this issue in vivo. The knowledge that Eph receptor tyrosine kinases (RTKs) function as ephrin receptors and that UNC40 and UNC5 gene family members function as netrin receptors provides important clues for characterizing the intracel-lular signaling pathways activated by these guidance cues. The identification of semaphorin receptors, however , is only now beginning to point the way toward elucidating the signaling pathways used by semaphorins during neural development to direct extending growth Figure 1. Semaphorins and Their Receptors cones away from inappropriate targets.The semaphorins are a large family of phylogenetically actions (arrows) identified thus far. The eight known semaphorin conserved secreted and transmembrane proteins (see classes are shown (1–7 plus " V " [viral semaphorins]), as are the two Figure 1 for description of the semaphorin family), many known plexin classes and the neuropilins. All vertebrate plexins except VESPR have the same overall structure as that depicted for members of which can mediate repulsive guidance Drosophila Plexin A. Amino-terminal labels denote specific proteins events during neural development (Mark et al., 1997). discussed in text, and color coding denotes structural motifs. The All semaphorins have a conserved ‫005ف‬ amino acid structural motifs in the extracellular domains of neuropilins are not extracellular semaphorin (Sema) domain. To date within related in any way to the extracellular domains of plexins. Ig, im-best characterized functionally at the cellular level. For example, extensive work from many groups demonstrates that semaphorin III/collapsin-1 (Sema III) in verte-cues, showing that semaphorins are bifunctional (Wong brates can function as a potent chemorepellent both in vitro and in vivo and strongly suggests that other class Several class 3 semaphorins bind to and require neu-3 semaphorins are likely to function in a similar fashion. …