title: Subrepellent doses of Slit1 promote Netrin-1 chemotactic responses in subsets of axons.
abstract: BACKGROUND
  Axon pathfinding is controlled by guidance cues that elicit specific attractive or repulsive responses in growth cones. It has now become clear that some cues such as Netrin-1 can trigger either attraction or repulsion in a context-dependent manner. In particular, it was recently found that the repellent Slit1 enables the attractive response of rostral thalamic axons to Netrin-1. This finding raised the intriguing possibility that Netrin-1 and Slit1, two essential guidance cues, may act more generally in an unexpected combinatorial manner to orient specific axonal populations. To address this major issue, we have used an innovative microfluidic device compatible not only with dissociated neuronal cultures but also with explant cultures to systematically and quantitatively characterize the combinatorial activity of Slit1 and Netrin-1 on rostral thalamic axons as well as on hippocampal neurons.
  
  
  RESULTS
  We found that on rostral thalamic axons, only a subthreshold concentration of the repellent Slit1 triggered an attractive response to a gradient of Netrin-1. On hippocampal neurons, we similarly found that Slit1 alone is repulsive and a subthreshold concentration of Slit1 triggered a potent attractive or repulsive behavioral response to a gradient of Netrin-1, depending on the nature of the substrate.
  
  
  CONCLUSIONS
  Our study reveals that at subthreshold repulsive levels, Slit1 acts as a potent promoter of both Netrin-1 attractive and repulsive activities on distinct neuronal cell types, thereby opening novel perspectives on the role of combinations of cues in brain wiring.
authors.affiliation: University Bordeaux, IINS, UMR 5297, F-33000, Bordeaux, France. isabelle.dupin@u-bordeaux.fr.|CNRS, IINS, UMR 5297, F-33000, Bordeaux, France. isabelle.dupin@u-bordeaux.fr.|Centre de Recherche Cardio-thoracique de Bordeaux, U1045, CIC 0005, INSERM, University Bordeaux, F-33000, Bordeaux, France. isabelle.dupin@u-bordeaux.fr.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Dupin
authors.affiliation: ENS, IBENS, INSERM U1024, CNRS UMR8197, 46 rue d'Ulm, 75005, Paris, France. lokmane@biologie.ens.fr.
authors.forename: Ludmilla
authors.initials: L
authors.lastname: Lokmane
authors.affiliation: Institut Curie, Laboratoire de Physico-Chimie, CNRS UMR 168, Université Pierre et Marie Curie-Paris 6, 75005, Paris, France. maxime.dahan@curie.fr.
authors.forename: Maxime
authors.initials: M
authors.lastname: Dahan
authors.affiliation: ENS, IBENS, INSERM U1024, CNRS UMR8197, 46 rue d'Ulm, 75005, Paris, France. garel@biologie.ens.fr.
authors.forename: Sonia
authors.initials: S
authors.lastname: Garel
authors.affiliation: University Bordeaux, IINS, UMR 5297, F-33000, Bordeaux, France. vincent.studer@u-bordeaux.fr.|CNRS, IINS, UMR 5297, F-33000, Bordeaux, France. vincent.studer@u-bordeaux.fr.
authors.forename: Vincent
authors.initials: V
authors.lastname: Studer
mesh_terms: D000818:Animals; D001369:Axons / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D018929:Cell Culture Techniques / Q000295:instrumentation; D002478:Cells, Cultured; D002633:Chemotaxis / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D056656:Lab-On-A-Chip Devices; D007797:Laminin / Q000494:pharmacology; D051379:Mice; D046210:Microfluidic Analytical Techniques; D009414:Nerve Growth Factors / Q000494:pharmacology*; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D000075388:Netrin-1; D009928:Organ Specificity; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013788:Thalamus / Q000166:cytology; D025521:Tumor Suppressor Proteins / Q000494:pharmacology*
chemical_list: D007797:Laminin; C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; C000617353:Ntn1 protein, mouse; C000617354:Ntn1 protein, rat; D011994:Recombinant Proteins; C492289:SLIT1 protein, human; C120010:Slit1 protein, mouse; D025521:Tumor Suppressor Proteins; D000075388:Netrin-1