p190RhoGAP Filters Competing Signals to Resolve Axon Guidance Conflicts

Neuron. 2019 May 8;102(3):602-620.e9. doi: 10.1016/j.neuron.2019.02.034. Epub 2019 Mar 19.


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.

Keywords: Cxcr4; DCC; GTPase activity; Netrin-1; axon guidance; gating cell signals; motor neuron; p190RhoGAP; spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anterior Horn Cells / metabolism
  • Axon Guidance / genetics*
  • DCC Receptor / metabolism*
  • GTPase-Activating Proteins / genetics*
  • Mice
  • Motor Neurons / metabolism*
  • Mouse Embryonic Stem Cells
  • Muscle, Skeletal / innervation*
  • Mutation
  • Netrin-1 / metabolism*
  • Repressor Proteins / genetics*


  • Arhgap35 protein, mouse
  • DCC Receptor
  • Dcc protein, mouse
  • GTPase-Activating Proteins
  • Ntn1 protein, mouse
  • Repressor Proteins
  • Netrin-1