Excess repulsion in a Robo mutant (left) is decreased by GEF64C (right).

Neuronal growth cones are guided by both attractive and repulsive signals during development. Until now, one part of the guidance signaling system appeared relatively straightforward: Rac GTPases stimulate attraction, while Rho GTPases stimulate repulsion. But on page 1117, Bashaw et al. describe the activity of a new Rho guanine nucleotide exchange factor in Drosophila melanogaster, GEF64C, that can stimulate axon attraction.

The authors started with flies expressing a chimeric receptor, which caused excessive crossing of the midline of the central nervous system. Overexpression of GEF64C exacerbated this phenotype. Bashaw et al. knew that the established attractants and repellents emanate from the midline, so they interpreted the new phenotye as resulting from increased attraction to the midline. GEF64C overexpression also promoted midline crossing in a mutant that otherwise shows excessive repulsion away from the midline.

The GEF64C effects were diminished by a dominant-negative RhoA, but unaffected by dominant-negative Rac1 or Cdc42. It is unclear how RhoA might promote attraction. But, based on the convergence of multiple guidance signals downstream of receptors, this type of downstream machinery presents an intriguing possibility for therapies that aim to stimulate axon regrowth in injured humans. ▪