Interplay between distinct axon guidance molecules in the development of the thalamocortical connectivity: a role for slit1 and netrin-1

• Autores: Eduardo Leyva Díaz
• Directores de la Tesis: Guillermina López Bendito (dir. tes.)
• Lectura: En la Universidad Miguel Hernández de Elche ( España ) en 2014
• Idioma: español
• Tribunal Calificador de la Tesis: Oscar Marin Parra (presid.), Eduardo de Puelles Martínez de la Torre (secret.), R. Jeroen Pasterkamp (voc.), Fernando Moya Rodríguez (voc.), Klas Kullander (voc.)
• Materias:
  • Química
    • Bioquímica
      • Biología molecular
  • Ciencias de la vida
    • Biología animal (zoología)
      • Desarrollo animal
    • Biología celular
      • Cultivo celular
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• Resumen

  • 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 this study, we have used thalamocortical axons (TCA) as a model to investigate how guidance cues are integrated during the development of complex longitudinal tracts. TCAs convey sensory and motor information to the neocortex showing a rostrocaudal topographic organization initially established within the ventral telencephalon. Here, we show that this topography is set in a small hub, the corridor, which contains matching rostrocaudal gradients of Slit1 and Netrin-1. Using combinations of in vivo, ex vivo and in vitro assays, we demonstrate that Slit1 acts as a rostral repellent that positions intermediate TCA (iTCA). On rostral TCA (rTCA), while Slit1 is also repulsive and Netrin-1 has no chemotrophic activity, the two factors combined generate an emergent attraction. These results show that Slit1 has a dual context-dependent role in TCA pathfinding as a single gradient of Slit1 organizes the topographic fanning of two thalamic populations by triggering distinct responses. In rTCA, the attractive response to the guidance cue Netrin-1 is controlled by Slit/Robo1 signaling and by FLRT3, a novel co-receptor 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 Deleted in colorectal carcinoma (DCC) through the activation of protein kinase A (PKA). Finally, the absence of FLRT3 produces defects in axon guidance in vivo. Our study thus provides a novel framework to explain how a limited set of guidance cues can generate a vast diversity of axonal responses necessary for proper wiring of the nervous system.