Slit Branches Out A Secreted Protein Mediates Both Attractive and Repulsive Axon Guidance

grow to the midline because attractive molecules such as netrins are expressed there. Midline repulsive activi-Slit is a large, modular extracellular matrix protein con-ties may also be necessary, however, to prevent longitu-taining four arrays of leucine-rich repeat (LRR) se-dinal axons that express attractive netrin receptors from quences, followed by a string of epidermal growth factor crossing the midline. Furthermore, repulsion is required (EGF)–like repeats (Rothberg et al., 1990). slit mutations to allow the growth cones of commissural neurons to were first identified in the famous Nü sslein-Volhard/ leave the midline as they travel across the CNS, and Wieschaus patterning screen because they affect exter-to keep them from later returning to the midline. The nal midline structures in the Drosophila embryo (Nü ss-transmembrane protein Roundabout (Robo), which is lein-Volhard et al., 1984). Drosophila and C. elegans expressed on neuronal growth cones and axons, is a have a single slit gene, while humans and rats have three receptor for this midline repulsive signal in Drosophila. from the midline and cross over to the contralateral side Slit is expressed by midline glia in the fly embryo; and of the CNS, while commissural axons follow looping in slit mutants these glia are ventrally displaced and the paths around the midline, crossing it multiple times (Kidd ladder-like axon scaffold of the central nervous system et al. 1998a; Figure 1B). (CNS) collapses down to a single tract at the midline Robo function is controlled by the Commissureless (Figure 1B). Mutations that delete all midline glia pro-(Comm) protein. Comm is also a transmembrane protein, duce similar phenotypes, so Slit was thought to be pri-but it is expressed on midline glia and is transferred to marily involved in the control of midline cell fates. The commissural axons by an unknown mechanism (Tear et collapse of the axon ladder was assumed to be a sec-al., 1996). Comm causes degradation or downregulation ondary consequence of these cell fate changes. A series of Robo in the commissures. After commissural axons of recent papers in, however, now show that Slit's major functions are likely to be in the direct control of axon guidance decisions. Remarkably, Slit has been shown to have at least two distinct guidance activities, discovered through complementary genetic and biochemical approaches. Analysis of mutant phenotypes in Drosophila embryos showed that Slit is likely to represent a postulated activity at the midline that repels growth cones (Kidd et al., 1999). …