p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts

The rich functional diversity of the nervous system is founded in the specific connectivity of the underlying neural circuitry. Neurons are often preprogrammed to respond to multiple axon guidance signals because they use sequential guideposts along their pathways, but this necessitates a strict spatiotemporal regulation of intracellular signaling to ensure the cues are detected in the correct order. We performed a mouse mutagenesis screen and identified the Rho GTPase antagonist p190RhoGAP as a critical regulator of motor axon guidance. Rather than acting as a compulsory signal relay, p190RhoGAP uses a non-conventional GAP-independent mode to transiently suppress attraction to Netrin-1 while motor axons exit the spinal cord. Once in the periphery, a subset of axons requires p190RhoGAP-mediated inhibition of Rho signaling to target specific muscles. Thus, the multifunctional activity of p190RhoGAP emerges from its modular design. Our findings reveal a cell-intrinsic gate that filters conflicting signals, establishing temporal windows of signal detection. [Display omitted] •p190 is a context-dependent gate for Netrin-DCC signaling•Distinct temporal activities of p190 emerge from a modular domain organization•p190 is a cell intrinsic signal-detection filter•Suppression of incongruous directional signals prevents miswiring Axon growth requires an enormous signaling matrix as the underlying code for building the nervous system. In a genetic screen, Bonanomi et al. identify p190RhoGAP as a critical regulatory switch that silences contextually inappropriate guidance signals for precise wiring of neuronal connections.