Eduardo Leyva-Díaz1, Daniel del Toro2, Maria José Menal3, Serafi Cambray3, Rafael Susín1, Marc Tessier-Lavigne4, Rüdiger Klein2, Joaquim Egea5, Guillermina López-Bendito6. 1. Instituto de Neurociencias de Alicante, CSIC and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain. 2. Department of Molecules - Signals - Development, Max Planck Institute of Neurobiology, 82152 Martinsried, Germany; Munich Cluster for Systems Neurology (SyNergy), 80336 Munich, Germany. 3. Molecular and Developmental Neurobiology Group, IRBLLEIDA, University of Lleida, 25198 Lleida, Spain. 4. Laboratory of Brain Development and Repair, Rockefeller University, New York, NY 10065, USA. 5. Molecular and Developmental Neurobiology Group, IRBLLEIDA, University of Lleida, 25198 Lleida, Spain. Electronic address: joaquim.egea@cmb.udl.cat. 6. Instituto de Neurociencias de Alicante, CSIC and Universidad Miguel Hernández, 03550 Sant Joan d'Alacant, Spain. Electronic address: g.lbendito@umh.es.
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.
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: Minkyung Kim; Tatiana Fontelonga; Andrew P Roesener; Haeram Lee; Suman Gurung; Philipe R F Mendonca; Grant S Mastick Journal: Dev Biol Date: 2014-12-18 Impact factor: 3.582
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