The Robo3 receptor, a key player in the development, evolution, and function of commissural systems

Roundabout receptors are known to mediate Slit-dependent repulsive signaling. However in vertebrates, mounting evidence suggest that Robo3 is an unconventional Robo receptor regarding both its expression and function. From its initial description, the Robo3 receptor has been tightly associated with the development of specific axons, called commissural, that connect both sides of the nervous system. Many studies using transgenic mouse models showed that Robo3 expression is mandatory for commissural axon guidance to the floor plate. Moreover, mutations in human ROBO3 are responsible for a rare neurological disease in which patients also display midline crossing defects. Robo3 was initially thought to counteract Slit/Robo repulsion. However, recent studies support an alternative model where Robo3 potentiates midline attraction. These studies support a complex, central and multifaceted role of Robo3 in controlling the development of commissural circuits. Furthermore, the analysis of Robo3 evolution in vertebrates points out the specificity of this receptor in the mammalian lineage, suggesting mechanistic and functional divergence of Robo3 in mammals compared to a more traditional function in other vertebrates. Here, we review the current knowledge about Robo3 function, from the regulation of its expression to signaling. We also present evidence for a high variability of Robo3 splice variants in vertebrates. © 2016 Wiley Periodicals, Inc. Develop Neurobiol 77: 876-890, 2017.