The importance of precise axon guidance for the wiring of the nervous system has long been recognized, and studies in flies and vertebrates have brought to light a multitude of molecules that allow growth cones to navigate the developing nervous system. But axons are not the only neuronal projections that need guidance, as Furrer et al. report in Nature Neuroscience. Dendrites also need to be accurately steered to their targets to make appropriate synaptic connections, and this study shows that they rely on some of the same cues as axons.

In wild-type Drosophila embryos, the aCC (red) and RP3 (blue) neurons extend dendrites on both sides of the midline (dashed line). In the comm mutant, the aCC dendrites that normally cross the midline are lost or reduced. In the robo mutant, the RP3 dendrites grow towards the midline and often wrap around it. Reproduced, with permission, from Furrer et al., Nature Neuroscience © (2003) Macmillan Magazines Ltd.

In the Drosophila central nervous system, two sets of molecules help to determine whether axons project contralaterally (across the midline) or ipsilaterally (away from or parallel to the midline). Slit and its receptor Robo mediate repulsion at the midline, thereby preventing axons from crossing, whereas Netrin and its receptor Frazzled mediate attraction, allowing axons to cross the midline to form commissural tracts. Furrer et al. asked whether these molecules also regulate midline crossing of dendrites. In addition, they studied the effects on dendritic guidance of mutations in commissureless (comm), a gene that codes for a protein that counteracts Slit/Robo-mediated repulsion.

In comm mutants, the number of contralaterally-projecting axons is considerably reduced. Furrer et al. now show that many populations of dendrites that would normally project contralaterally also fail to cross the midline in these mutants. A similar phenomenon was seen in netrin and frazzled mutant embryos. In robo mutants, the commissures are thickened, and it was previously thought that this was largely due to increased crossing and re-crossing of axons. However, Furrer et al. show that aberrant crossing of dendrites also contributes significantly to this phenotype.

The dendritic guidance defects in frazzled and robo mutants could be rescued in individual neurons by restoring the function of the corresponding gene, indicating that Frazzled and Robo act cell-autonomously to regulate the response of growing dendrites to guidance cues in their environment. The authors also found that in rescued frazzled mutants, Frazzled protein was found in dendrites that were able to cross the midline, whereas in rescued robo mutants, Robo was localized to dendrites that were repelled by the midline.

These findings raise an intriguing question about the regulation of Robo and Frazzled expression in developing neurons. Many neurons extend several axonal and dendritic processes, of which some project contralaterally and some ipsilaterally. Together with the observations on the subcellular localization of Robo and Frazzled in rescued mutant neurons, this indicates that Robo and Frazzled are probably targeted differentially to processes that emanate from the same cell. The question of how this is achieved will undoubtedly provide a focus for future investigations.