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      SAX-3 (Robo) and UNC-40 (DCC) Regulate a Directional Bias for Axon Guidance in Response to Multiple Extracellular Cues

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          Abstract

          Axons in Caenorhabditis elegans are guided by multiple extracellular cues, including UNC-6 (netrin), EGL-20 (wnt), UNC-52 (perlecan), and SLT-1 (slit). How multiple extracellular cues determine the direction of axon guidance is not well understood. We have proposed that an axon's response to guidance cues can be modeled as a random walk, i.e., a succession of randomly directed movement. Guidance cues dictate the probability of axon outgrowth activity occurring in each direction, which over time creates a directional bias. Here we provide further evidence for this model. We describe the effects that the UNC-40 (DCC) and SAX-3 (Robo) receptors and the UNC-6, EGL-20, UNC-52, and SLT-1 extracellular cues have on the directional bias of the axon outgrowth activity for the HSN and AVM neurons. We find that the directional bias created by the cues depend on UNC-40 or SAX-3. UNC-6 and EGL-20 affect the directional bias for both neurons, whereas UNC-52 and SLT-1 only affect the directional bias for HSN and AVM, respectively. The direction of the bias created by the loss of a cue can vary and the direction depends on the other cues. The random walk model predicts this combinatorial regulation. In a random walk a probability is assigned for each direction of outgrowth, thus creating a probability distribution. The probability distribution for each neuron is determined by the collective effect of all the cues. Since the sum of the probabilities must equal one, each cue affects the probability of outgrowth in multiple directions.

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          Most cited references26

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          The molecular biology of axon guidance.

          Neuronal growth cones navigate over long distances along specific pathways to find their correct targets. The mechanisms and molecules that direct this pathfinding are the topics of this review. Growth cones appear to be guided by at least four different mechanisms: contact attraction, chemoattraction, contact repulsion, and chemorepulsion. Evidence is accumulating that these mechanisms act simultaneously and in a coordinated manner to direct pathfinding and that they are mediated by mechanistically and evolutionarily conserved ligand-receptor systems.
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            Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance.

            Extending axons in the developing nervous system are guided in part by repulsive cues. Genetic analysis in Drosophila, reported in a companion to this paper, identifies the Slit protein as a candidate ligand for the repulsive guidance receptor Roundabout (Robo). Here we describe the characterization of three mammalian Slit homologs and show that the Drosophila Slit protein and at least one of the mammalian Slit proteins, Slit2, are proteolytically processed and show specific, high-affinity binding to Robo proteins. Furthermore, recombinant Slit2 can repel embryonic spinal motor axons in cell culture. These results support the hypothesis that Slit proteins have an evolutionarily conserved role in axon guidance as repulsive ligands for Robo receptors.
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              Slit is the midline repellent for the robo receptor in Drosophila.

              Previous studies suggested that Roundabout (Robo) is a repulsive guidance receptor on growth cones that binds to an unknown midline ligand. Here we present genetic evidence that Slit is the midline Robo ligand; a companion paper presents biochemical evidence that Slit binds Robo. Slit is a large extracellular matrix protein expressed by midline glia. In slit mutants, growth cones enter the midline but never leave it; they abnormally continue to express high levels of Robo while at the midline. slit and robo display dosage-sensitive genetic interactions, indicating that they function in the same pathway. slit is also required for migration of muscle precursors away from the midline. Slit appears to function as a short-range repellent controlling axon crossing of the midline and as a long-range chemorepellent controlling mesoderm migration away from the midline.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                15 October 2014
                : 9
                : 10
                : e110031
                Affiliations
                [1]Department of Pathology, Rutgers Robert Wood Johnson Medical School, Piscataway, New Jersey, United States of America
                Trinity College Dublin, Ireland
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: XT WGW. Performed the experiments: XT. Analyzed the data: XT WGW. Contributed reagents/materials/analysis tools: XT WGW. Wrote the paper: XT WGW.

                Article
                PONE-D-14-39240
                10.1371/journal.pone.0110031
                4198195
                25333948
                147aa494-c8a5-47b2-8c06-4b6016879627
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 September 2014
                : 12 September 2014
                Page count
                Pages: 12
                Funding
                This work was supported by National Institutes of Health grants R01 NS033156 and R01 NS061805, and grants from the New Jersey Commission on Spinal Cord. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Cell Biology
                Signal Transduction
                Axon Guidance Receptors
                Developmental Biology
                Morphogenesis
                Neurodevelopment
                Genetics
                Animal Genetics
                Invertebrate Genetics
                Gene Function
                Neuroscience
                Cellular Neuroscience
                Axon Guidance
                Axon Guidance Receptor Genes
                Chemoattractant Axon Guidance
                Pioneer Axons
                Developmental Neuroscience
                Organisms
                Animals
                Invertebrates
                Nematoda
                Caenorhabditis
                Caenorhabditis Elegans
                Custom metadata
                The authors confirm that all data underlying the findings are fully available without restriction. All relevant data are within the paper and its Supporting Information files.

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                Uncategorized

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