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Dscam Switches Slit Repulsion To Mild Attraction Via Robo Receptors
Biochemistry and Molecular Biology
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Axon guidance is a critical part of neural development, the process thatgenerates and shapes the nervous system, from the earliest stages ofembryogenesis to the last years of life. Axons navigate to reach their correcttargets via different axon guidance cues, such as Netrins and Slits. The axonalgrowth cone contains receptors that distinguish these guidance molecules andtranslates them into attractive or repulsive responses. Slit repels axons from theCNS midline by binding to the Robo (Roundabout) receptor. Netrin acts as anattractant through fra/DCC/Unc-40 and Dscam (Down syndrome cell adhesionmolecule) receptors. However, genetic evidence shows that Dscam alsoresponds to other ligand(s).We have identified Slit as an additional ligand for Dscam using both celloverlay and immunoprecipitation assays. Our results show that the Dscam onlybinds to the Slit N-terminal fragment (Slit-N), in a domain distinct from the Robobinding site. I have demonstrated that Robo preferentially binds full length Slit(Slit-FL), but in the presence of Dscam binds Slit-N. We believe that this Slit-Ndependent Dscam-Robo complex modifies Robo signaling.In vivo, slit-FL and slit-N transgenes have differential effects on motorneuron innervation of muslces that are mediated by Dscam. Overexpression ofslit-FL and slit-N at the CNS midline in a robo mutant background leads to anincrease in axon attraction to the midline. We interpret this result as evidencethat Slit has an attractive as well as a repulsive function. To test the hypothesisiithat Dscam can act as an attractive receptor for Slit, we employed a range of slittransgenes to analyze attractive functions of slit in axon guidance. Our dataargues that Slit needs to be processed to act as an axonal attractant in vivo. Weexamined the consequence of removing the Robo binding domain (LRR2) fromSlit in vivo, hoping to observe the attractive function masked by Slit’s repulsiveactivity. Instead, the transgene appears only to inhibit Dscam activity, supportinga model that Dscam requires Robo as a co-receptor.Our data suggests that Dscam binds to proteolytically processed Slit andconverts repulsion to mild attraction in the presence of Robo receptors. Our workalso suggests that, as seen for other ligands, Slit can act as both an attractantand repellent via distinct receptors, and indicates how the complexity of thenervous system can arise through a relatively small number of ligands.