C-elegans VAB-8 and UNC-73 regulate the SAX-3 receptor to direct cell and growth-cone migrations

During nervous system development, a small number of conserved guidance cues and receptors regulate many axon trajectories. How could a limited number of cues and receptors regulate such complex projection patterns? One way is to modulate receptor function. Here we show that the Caenorhabditis elegans kinesin-related protein VAB-8L, which is necessary and sufficient for posterior cell and growth-cone migrations, directs these migrations by regulating the levels of the guidance receptor SAX-3 ( also known as robo). Genetic experiments indicate that VAB-8L and the Rac guanine nucleotide exchange factor activity of UNC-73 ( trio) increase the ability of the SLT-1 ( slit) and UNC-6 ( netrin) guidance pathways to promote posterior guidance. The observations of higher SAX-3 receptor abundance in animals with increasing amounts of VAB-8L, and of physical interactions between UNC-73 and both VAB-8L and the intracellular domain of the SAX- 3, support a model whereby VAB-8L directs cell and growth- cone migrations by promoting localization of guidance receptors to the cell surface.