Cross GTPase-activating protein (CrossGAP)/Vilse links the Roundabout receptor to Rac to regulate midline repulsion

TLDR

GTPase‑activating proteins and guanine exchange factors regulate Rho-family GTPases, which are crucial for axon guidance. A functional genomic screen in Drosophila identified the Rho-family GAP CrossGAP (CrGAP) as a mediator of Roundabout receptor–driven repulsive axon guidance. CrGAP physically associates with Robo, and its dosage‑sensitive interactions with Robo and Rac—where gain‑of‑function phenocopies loss of either protein—demonstrate that CrGAP transduces Robo signals to modulate Rac‑dependent cytoskeletal changes at the midline.

Abstract

The regulators of the Rho-family GTPases, GTPase-activating proteins (GAPs) and guanine exchange factors (GEFs), play important roles in axon guidance. By means of a functional genomic study of the Rho-family GEFs and GAPs in Drosophila , we have identified a Rho-family GAP, CrossGAP (CrGAP), which is involved in Roundabout (Robo) receptor-mediated repulsive axon guidance. CrGAP physically associates with the Robo receptor. Too much or too little CrGAP activity leads to defects in Robo-mediated repulsion at the midline choice point. The CrGAP gain-of-function phenotype mimics the loss-of-function phenotypes of both Robo and Rac. Dosage-sensitive genetic interactions among CrGAP, Robo, and Rac support a model in which CrGAP transduces signals downstream of Robo receptor to regulate Rac-dependent cytoskeletal changes.