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.

Slit-Robo signaling is also critical for many neurodevelopmental processes including formation of the olfactory tract, the optic nerve, and motor axon fasciculation.

[5][6] In addition, Slit-Robo signaling contributes to cell migration and the development of other tissues such as the lung, kidney, liver, muscle and breast.

A large-scale screen of the Drosophila genome for mutants that exhibited axon guidance defects led to the discovery of the roundabout (robo) mutation.

[12] Phylogenetic analysis reveals that all Robo receptors have evolved from a common ancestral protein, with many subsequent diversification events occurring independently in different lineages.

In vertebrates, Robo1 undergoes complex alternative splicing, generating several isoforms including DUTT1, a variant that has been identified as a tumor suppressor gene.

[20] Robo4 is expressed in the heart, liver, lungs, kidney, muscle, small intestine, endothelial cells, and largely in the placenta.

[22] In bilaterian animals, including insects and mammals, most axons in the CNS cross the midline during nervous system development.

In Drosophila, several signaling proteins downstream of Robo1 have been identified, including Enabled, Son of Sevenless (SOS), Rac, and Dock.

[27][28] The vertebrate Robo3/Rig1 homolog is a more distant relative of the Robo gene family, and is thought to play a distinct role in axonal guidance.

Recently, a genome-wide linkage study by Viding and colleagues (2010)reported that the Robo2 gene could be involved in developmental disorders such as psychopathy.

A defect in the Robo3/Rig1 protein results in horizontal gaze palsy with progressive scoliosis (HGPPS), a rare genetic disorder.

[35] During normal brain development, Robo3/Rig1 decreases sensitivity of Robo1 to Slit proteins, allowing the axon to grow past the midline.

In patients with HGPPS, the absence of Robo3/Rig1 prevents axons in the corticospinal tract and the trochlear nerve[33] from growing past the midline.