Roundabout (gene)
The Roundabout (Robo) family of proteins are single-pass transmembrane receptors that are highly conserved across many branches of the animal kingdom, from C. elegans to humans. They were first discovered in Drosophila, through a mutant screen for genes involved in axon guidance. The Drosophila roundabout mutant was named after its phenotype, which resembled the circular traffic junctions (see roundabout). The Robo receptors are most well known for their role in the development of the nervous system, where they have been shown to respond to secreted Slit ligands. One well-studied example is the requirement for Slit-Robo signaling in regulation of axonal midline crossing. Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation. In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast. Mutations in Robo genes have been linked to multiple neurodevelopmental disorders in humans.
A large-scale screen of the Drosophila genome for mutants that exhibited axon guidance defects led to the discovery of the roundabout (robo) mutation. In robo mutants, axons were observed to inappropriately cross and recross the midline. It was subsequently found that the secreted protein Slit was the ligand for the Roundabout receptor. Vertebrate Slit proteins were identified shortly after, and were shown to bind both vertebrate and Drosophila Robo receptors and to mediate axonal repulsion of spinal cord explants. It was several more years before a functional analysis of the vertebrate Slit and Robo mutants was performed; this analysis demonstrated that Slit-Robo signaling regulates commissural axon guidance in vertebrates as well. Interestingly, while the vertebrate receptors Robo1 and Robo2 signal repulsion in response to Slit to prevent inappropriate midline crossing, a novel function for Robo3/Rig1 was discovered; unlike the other Robo receptors, it is required to promote midline crossing.
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