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Roundabout (Robo) Gene

Axonal guidance
Most axons in the CNS cross the midline at some point during nervous system development. The Robo proteins are critical regulators of midline crossing across species. In Drosophila, Robo1 and Robo2 are required to keep ipsilaterally projecting axons from inappropriately crossing the midline, and to prevent contralateral axons from remaining stuck at the midline. In vertebrates, Robo1 and Robo2 are expressed in commisural axons, and act as repulsive receptors for the Slit ligands expressed by floor plate cells located at the midline. Robo3, while it also binds Slit, does not appear to play a major role in regulating midline crossing. Instead, it is required for a guidance decision after crossing. Upon exiting the midline, contralateral axons travel some distance before turning to project anteriorly or posteriorly. Robo3 is required for correct lateral pathway selection. In vertebrates, the Robo3/Rig1 is alternatively spliced to generate a protein that inhibits Robo1/2-mediated repulsion, effectively leading to the promotion of midline crossing. The exact mechanism by which Robo3 achieves this anti-repulsive activity is unknown.

Axonal guidance is initiated by the attraction of Robo1 and Robo2 to netrin. Growing axons with low expression of Robo1 are able to enter the midline, while those with high levels of Robo1 cannot. Once axons are in the midline, Robo receptors located on the axon bind the ligand Slit. This interaction results in a repulsive response, causing the axon to leave the midline. It is believed this interaction also prevents lingering in the midline, therefore driving the axons to cross the midline instead of retreating to the side of origin. When the axon exits the midline, Robo1 levels are increased, preventing further crossing of the midline.

In robo1 mutants, robo1 receptors are absent and the cell is unable to increase the expression of robo1 after the initial crossing of the midline. This leads to multiple midline crossings. In robo1,robo2 double mutants, axonal bundles collapse at the midline, forming one giant nerve fascicle which remains within the midline. This is identical to the phenotype of slit mutant embryos. In robo3 mutants, defects are observed in the organization of lateral bundles, as too many remain closer to the midline than they should be. Robo2 also contributes to lateral pathway selection.

Robo receptors have also been shown to be crucial regulators of many other axon pathfinding decisions during development, including the projection of retinal axons in the optic tract, and of olfactory axons in the olfactory epithelium.

Expression
Robo1 is expressed generally throughout the central nervous system. Robo2 is expressed the greatest in the adult ovary and in most regions of the adult and fetal brain. Intermediate expression of Robo2 is seen in the fetal liver and adult lung, kidney, spleen, testis, and spinal cord. Robo3 is found in the hindbrain. Robo4 is expressed in the heart, liver, lungs, kidney, muscle, small intestine, endothelial cells, and largely in the placenta.