Showing nerve cells the way forward
Establishment of nerve connections is a complex process involving interaction between guidance receptors and extracellular signals. Called guidance cues, the signals are normally presented in an overlapping fashion and can trigger opposing effects such as repulsion and adhesion. The 'Genetic analysis of a novel family of repulsive guidance cues acting through Unc5 receptors' (FLRT IN NEUROBIOLOGY) project turned its attention to FLRT proteins, an emerging protein family implicated in neuronal development. In collaborations with other labs at CSIC & Universidad Miguel Hernández and University of Lleida (Spain), the University of Oxford (United Kingdom) and Goethe University (Germany), they have discovered ingenious neurodevelopmental mechanisms. Project researchers looked at the effect of overexpression of FLRT3 on positioning of intermediate thalmic axons. Their results indicated, for the first time, that FLRT3 is an important modulator in axon guidance as a glut of the protein drove axons into a more frontal position. As FLRTs are unique in that they can act as both homophilic cell adhesion molecules and repulsive ligands for receptors, the researchers designed mutants that disrupt either of these opposing functions. Based on crystal structures of both FLRTs and Unc5 receptors, they looked at the function of FLRTs in neuronal and cardiac development. In stripe assays specifically designed for the study of axonal guidance, the researchers found that FLRT3 acts as a repulsive guidance cue on axons from the thalamocortex. Moreover, FLRT3 can signal in a parallel fashion through both Unc5 and FLRT3 to attenuate the Unc5-dependent repulsive signal. The repulsive and adhesive signals can also delay radial migration of neurons. In contrast, FLRT3 can also modulate the tangential distribution of pyramidal neurons. FLRT3 is a protein with a wide range of functions, including vascular development. The scientists discovered that the fundamental adhesive/repulsive functions of FLRTs are conserved in cultures of vascular endothelial cells expressing FLRT3 and Unc5B. FLRT3 repels Unc5B-expressing endothelial tip cells and controls vascular branching in the developing mouse eye. The work of FLRT IN NEUROBIOLOGY promises application in both neurobiology and vascular biology fields. A highly conserved group of proteins, FLRT research could also impact on other fields as many tissues, including the heart, kidney and lung, express this multifunctional protein family.
Keywords
Nerve cells, guidance cues, repulsion, adhesion, FLRT protein
