title: FLRT3 is a Robo1-interacting protein that determines Netrin-1 attraction in developing axons.
abstract: BACKGROUND
  Guidance molecules are normally presented to cells in an overlapping fashion; however, little is known about how their signals are integrated to control the formation of neural circuits. In the thalamocortical system, the topographical sorting of distinct axonal subpopulations relies on the emergent cooperation between Slit1 and Netrin-1 guidance cues presented by intermediate cellular targets. However, the mechanism by which both cues interact to drive distinct axonal responses remains unknown.
  
  
  RESULTS
  Here, we show that the attractive response to the guidance cue Netrin-1 is controlled by Slit/Robo1 signaling and by FLRT3, a novel coreceptor for Robo1. While thalamic axons lacking FLRT3 are insensitive to Netrin-1, thalamic axons containing FLRT3 can modulate their Netrin-1 responsiveness in a context-dependent manner. In the presence of Slit1, both Robo1 and FLRT3 receptors are required to induce Netrin-1 attraction by the upregulation of surface DCC through the activation of protein kinase A. Finally, the absence of FLRT3 produces defects in axon guidance in vivo.
  
  
  CONCLUSIONS
  These results highlight a novel mechanism by which interactions between limited numbers of axon guidance cues can multiply the responses in developing axons, as required for proper axonal tract formation in the mammalian brain.
authors.affiliation: Instituto de Neurociencias de Alicante, CSIC and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Leyva-Díaz
authors.affiliation: Department of Molecules - Signals - Development, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: del Toro
authors.affiliation: Molecular and Developmental Neurobiology Group, IRBLLEIDA, University of Lleida, 25198 Lleida, Spain.
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Menal
authors.affiliation: Molecular and Developmental Neurobiology Group, IRBLLEIDA, University of Lleida, 25198 Lleida, Spain.
authors.forename: Serafi
authors.initials: S
authors.lastname: Cambray
authors.affiliation: Instituto de Neurociencias de Alicante, CSIC and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Susín
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: Department of Molecules - Signals - Development, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany.
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Klein
authors.affiliation: Molecular and Developmental Neurobiology Group, IRBLLEIDA, University of Lleida, 25198 Lleida, Spain. Electronic address: joaquim.egea@cmb.udl.cat.
authors.forename: Joaquim
authors.initials: J
authors.lastname: Egea
authors.affiliation: Instituto de Neurociencias de Alicante, CSIC and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain. Electronic address: g.lbendito@umh.es.
authors.forename: Guillermina
authors.initials: G
authors.lastname: López-Bendito
mesh_terms: D000818:Animals; D001369:Axons / Q000502:physiology*; D000075389:DCC Receptor; D018507:Gene Expression Regulation, Developmental; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D000075388:Netrin-1; D009924:Organ Culture Techniques; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000166:cytology / Q000254:growth & development / Q000502:physiology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097905:Roundabout Proteins
chemical_list: D000075389:DCC Receptor; D008562:Membrane Glycoproteins; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075388:Netrin-1; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; D025521:Tumor Suppressor Proteins; D000097905:Roundabout Proteins; C501910:Dcc protein, mouse; C514260:FLRT3 protein, mouse; C000617353:Ntn1 protein, mouse; C120010:Slit1 protein, mouse