Signaling by Slit
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Signaling by Slit
Neuronal growth cones in the developing nervous system are guided to their targets by attractive and repulsive guidance molecules, which include members of the Netrin, Semaphorin, Ephrin, and Slit protein families. Slit is a ~200 KD secretory protein originally shown to be expressed by neurons and glial cells. Slit was originally identified in Drosophila as an extracellular cue to guide axon pathfinding, to promote axon branching, and to control neuronal migration (Ref.1).

Mammalian Slit consists of three members, Slit1, Slit2, and Slit3. All are expressed in the nervous system but Slit1 is specifically expressed in brain, whereas Slit2 and Slit3 are expressed in brain as well as kidney, lung, heart, spleen, and lymph nodes. A prototypical Slit protein contains an N-terminal signal peptide, four LRRs (Leucine-Rich Repeats), seven (in Drosophila Slit) or nine (in vertebrate Slits) EGF-like repeats, a Laminin G-domain, and a C-terminal cysteine-rich knot. The LRRs are sufficient for Slit interaction with the receptor (Ref.2). The molecular target for Slit is a repulsive guidance transmembrane receptor known as the Robo (Roundabout) receptor named after robo mutant flies, in which commissural axons cross and recross the midline in the manner of a roundabout. Robo is a cell surface receptor that is responsible for the repulsive effect of Slit. Robo is a single-pass transmembrane protein. It contains five Ig (Immunoglobulin) domains and three FNIII (Fibronectin Type-III) repeats in its extracellular part. The cytoplasmic tails of Drosophila and human Robo1 contain four short blocks of conserved cytoplasmic motifs CC0, CC1, CC2 and CC3. There are two additional Robos: Robo2 and Robo3 that do not contain CC2 and CC3. All Robos are involved in multiple pathways of axon projection (including retinal and commissural axons) and neuronal migration (including the neocortex). The protein EnaH (Enabled Homolog) interacts with Robo to transduce part of Robo’s repulsive signal by binding to Robo’s CC2 motif. The non-receptor tyrosine kinase, Abl(Abelson), interacts with Robo through the CC3 region to antagonize Robo signaling—likely through a mechanism involving direct phosphorylation of the Robo receptor on the CC0 and CC1 motifs. It cooperates with multiple effectors, including the actin binding protein Capulet and CLASP (Cytoplasmic Linker Associated Protein) and simultaneously coordinates the dynamics of two major cytoskeletal systems to achieve growth cone repellent guidance. In addition to its role in negatively regulating Robo function, Abl can also promote repulsion downstream of multiple Robo receptors. The RhoGTPases and their upstream positive and negative regulators—GEFs (Guanine Nucleotide Exchange Factors) and GAPs (GTPase Activating Proteins)—play important roles in the control of growth cone guidance in the developing nervous system (Ref.3). The proline-rich CC3 motif in Robo binds directly to the SH3 domain in a subfamily of RhoGAPs—the srGAPs (Slit-Robo GTPase Activation Protein) and this interaction specifically inactivate CDC42 and RhoA, but not Rac1. srGAPs increase the intrinsic GTPase activity of CDC42, which converts the GTP-bound form of CDC42 into its GDP-bound form, therefore inactivating CDC42. Inactivation of CDC42 leads to a reduction in the activation of the N-WASP (Neuronal Wiskott - Aldrich syndrome Protein), thus decreasing the level of active ARP2/3 complex. Because active ARP2/3 promotes actin polymerization, the reduction of active CDC42 eventually decreases actin polymerization. The adaptor Nck/DOCK (Dedicator of Cytokinesis) and the downstream kinase PAK (p21-Activated Kinase) have also been implicated in the Slit/Robo pathway. Together, these molecules may either directly or indirectly introduce changes in the cytoskeletal components, including the re-organization of the actin and microtubule networks, and lead to directed cell migration. Although Robo seems to be the main receptor for Slit, it also functions through DCC (Deleted in Colorectal Cancer). Activation of Robo by Slit induces association with DCC involving CC1 in Robo and P3 (intracellular domain of DCC) in DCC. In leukocytes and mammalian cell lines, the Slit and Robo pathway has been found to inhibit cellular responses to multiple chemokines. In neurons, SDF1 (Stromal Derived Factor-1) functions as a chemoattractant for leukocytes through its receptor CXCR4 (Chemokine (C-X-C motif) Receptor-4) and inhibits responses to multiple repulsive guidance cues, including Slit and Semaphorin.

In the nervous system, the Slit/Robo receptor complex regulates the growth of axons and their projection to appropriate regions of the brain, and also functions as a repellent preventing axons from crossing non-target areas. Slit appears to function as a short-range signal that prevents axon re-crossing at the midline and as a long-rang cue that patterns the longitudinal pathways by signaling through a combinatorial code of Robo receptors. Slit can repel and inhibit the outgrowth, induce growth cone collapse and increase the fasciculation of RGC (Retinal Ganglion Cells) axons (Ref.4).