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

Slit is a large, modular extracellular matrix protein containing four arrays of leucine-rich repeat (LRR) sequences, followed by a string of epidermal growth factor (EGF)–like repeats (Rothberg et al. 1990). slit mutations were first identified in the famous Nüsslein-Volhard/Wieschaus patterning screen because they affect external midline structures in the Drosophila embryo ( Nüsslein-Volhard et al. 1984). Drosophila and C. elegans have a single slit gene, while humans and rats have three ( 5, 6, 11, 2 and 10). Slit is expressed by midline glia in the fly embryo; and in slit mutants these glia are ventrally displaced and the ladder-like axon scaffold of the central nervous system (CNS) collapses down to a single tract at the midline ( Figure 1B). Mutations that delete all midline glia produce similar phenotypes, so Slit was thought to be primarily involved in the control of midline cell fates. The collapse of the axon ladder was assumed to be a secondary consequence of these cell fate changes. A series of recent papers in Cell and Neuron ( 2, 9, 10, 17 and 12) and a paper in press in Development ( Battye et al. 1999), 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