SYD-1C,UNC-40 (DCC) and SAX-3 (Robo) Function Interdependently to Promote Axon Guidance by Regulating the MIG-2 GTPase

During development,axons must integrate directional information encoded by multiple guidance cues and their receptors. axon guidance receptors,such as unc-40 (dcc) and sax-3 (robo),can function individually or combinatorially with other guidance receptors to regulate downstream effectors. however,little is known about the molecular mechanisms that mediate combinatorial guidance receptor signaling. here,we show that unc-40,sax-3 and the syd-1 rhogap-like protein function interdependently to regulate the mig-2 (rac) gtpase in the hsn axon of c. elegans. we find that syd-1 mediates an unc-6 (netrin) independent unc-40 activity to promote ventral axon guidance. genetic analysis suggests that syd-1 function in axon guidance requires both unc-40 and sax-3 activity. moreover,the cytoplasmic domains of unc-40 and sax-3 bind to syd-1 and syd-1 binds to and negatively regulates the mig-2 (rac) gtpase. we also find that the function of syd-1 in axon guidance is mediated by its phylogenetically conserved c isoform,indicating that the role of syd-1 in guidance is distinct from its previously described roles in synaptogenesis and axonal specification. our observations reveal a molecular mechanism that can allow two guidance receptors to function interdependently to regulate a common downstream effector,providing a potential means for the integration of guidance signals. © 2015 xu et al.