Editors' ChoiceAxon Guidance

Rig-1 Prevents Premature Repulsion

Science's STKE  20 Apr 2004:
Vol. 2004, Issue 229, pp. tw144-TW144
DOI: 10.1126/stke.2292004TW144

The molecular mechanism by which commissural axons cross the midline only once on their path to the contralateral side is well understood in insects and involves the attraction of the growth cones to midline netrins at the same time the receptor Roundabout (Robo) to the repellent Slit is repressed by cytosolic sequestration owing to the activity of Commissureless (Comm), a transmembrane protein that binds to Robo. After crossing the midline, this repression is alleviated, and the growth cones are repelled by Slit. However, no homolog of Comm has been identified in vertebrates. Sabatier et al. show that in mouse and rat the divergent member of the vertebrate Robo family Rig-1 may serve as this repressor to repellent action. The extracellular ligand-binding domain of Rig-1 is conserved with other members of the Robo family, but the cytosolic domain lacks certain motifs common to other members of the Robo family. Rig-1 expression is high at the time that commissural axons are expressing Robo1 and when these axons are beginning to cross the midline. The Rig-1 protein is abundant on axons that have not crossed the midline and then is decreased after crossing. In Rig-1—/— mouse embryos, commissural axons failed to cross the midline. Explants of Rig-1—/— dorsal spinal cord showed that the axons were attracted to recombinant netrin, but that axons did not grow out toward wild-type floor plate tissue, which is a source of both netrin and slit. Addition of an antagonist to slit (based on the ectodomain of Robo2) allowed the mutant explants to extend axons toward the floor plate tissue. Recovery of midline crossing was observed by crossing the Rig-1 mutant mice with Slit mutant mice or with Robo1 mutant mice. Thus, Rig-1 appears to serve as the inhibitor of Robo activity, and in its absence, the axons become prematurely responsive to the repellent Slit and cannot cross the midline.

C. Sabatier, A. S. Plump, L. Ma, K. Brose, A. Tamada, F. Murakami, E. Y.-H. P. Lee, M. Tessier-Lavigne, The divergent Robo family protein Rig-1/Robo3 is a negative regulator of Slit responsiveness required for midline crossing by commissural axons. Cell 117, 157-169 (2004). [Online Journal]