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Diffusible chemorepellents play a major role in guiding developing axons towards their correct targets by preventing them from entering or steering them away from certain regions. Genetic studies in Drosophila revealed a novel repulsive guidance system that prevents inappropriate axons from crossing the CNS midline; this repulsive system is mediated by the Roundabout (Robo) receptors and their secreted ligand Slits. Three distinct slit genes (slit1, slit2 and slit3) and three distinct robo genes (robo1, robo2 and rig-1) have been cloned in mammals. In collagen gel co-cultures, Slit1 and Slit2 can repel and collapse olfactory axons. However, there is also some positive effect associated with Slits, as Slit2 stimulates the formation of axon collateral branches by NGF-responsive neurons of the dorsal root ganglia (DRG). Slit2 is a large ECM glycoproteins of about 200 kD, which is proteolytically processed into 140 kD N-terminal and 55-60 kD C-terminal fragments. Slit2 cleavage fragments appear to have different cell association characteristics, with the smaller C-terminal fragment being more diffusible and the larger N-terminal and uncleaved fragments being more tightly cell associated. This suggested that the different fragments might have different functional activities in vivo. We have begun to explore these questions by engineering mutant and truncated versions of hSlit2 representing the two cleavage fragments, N- and C-, and the uncleavable molecule and examining the activities of these mutants in binding and functional assays. We found that an axon's response to Slit2 is not absolute, but rather is reflective of the context in which the protein is encountered.
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PMID:Role of Slit proteins in the vertebrate brain. 1175 87

Slit was identified in Drosophila embryo as a gene involved in the patterning of larval cuticle. It was later shown that Slit is synthesized in the fly central nervous system by midline glia cells. Slit homologues have since been found in C. elegans and many vertebrate species, from amphibians, fishes, birds to mammals. A single slit was isolated in invertebrates, whereas there are three slit genes (slit1-slit3) in mammals, that have around 60% homology. All encodes large ECM glycoproteins of about 200 kDa (Fig. 1A), comprising, from their N terminus to their C terminus, a long stretch of four leucine rich repeats (LRR) connected by disulphide bonds, seven to nine EGF repeats, a domain, named ALPS (Agrin, Perlecan, Laminin, Slit) or laminin G-like module (see ref 17), and a cystein knot (Fig. 1A). Alternative spliced transcripts have been reported for Drosophila Slit2, human Slit2 and Slit3, and Slit1. Moreover, two Slit1 isoforms exist in zebrafish as a consequence of gene duplication. Last, in mammals, two Slit2 isoforms can be purified from brain extracts, a long 200 kDa one and a shorter 150 kDa form (Slit2-N) that was shown to result from the proteolytic processing of full-length Slit2. Human Slit and Slit3 and Drosophila Slit are also cleaved by an unknown protease in a large N-terminal fragment and a shorter C-terminal fragment, suggesting conserved mechanisms for Slit cleavage across species. Moreover, Slit fragments have different cell association characteristics in cell culture suggesting that they may also have different extents of diffusion, different binding properties, and, hence, different functional activities in vivo. This conclusion is supported by in vitro data showing that full-length Slit2 functions as an antagonist of Slit2-N in the DRG branching assay, and that Slit2-N, not full-length Slit2, causes collapse of OB growth cones. In addition, Slit1-N and full-length Slit1 can induce branching of cortical neurons (see below), but only full-length Slit1 repels cortical axons. Structure-function analysis in vertebrates and Drosophila demonstrated that the LRRs of Slits are required and sufficient to mediate their repulsive activities in neurons. More recent detailed structure function analysis of the LRR domains of Drosophila Slit, revealed that the active site of Slit (at least regarding its pro-angiogenic activity) is located on the second of the fourth LRR (LRR2), which is highly conserved between Slits. Slit can also dimerize through the LRR4 domain and the cystein knot.However, a Slit1 spliced-variant that lacks the cysteine knot and does not dimerize is still able to repel OB axons.
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PMID:Slits and their receptors. 1826 11