During neuronal development, axons form branches that allow a neuron to project to many targets. Colavita and Tessier-Lavigne have identified a signal in the worm Caenorhabditis elegans that acts as a branch-specific stop signal, giving new insight into how axonal branches are specified.

In C. elegans, a group of identified neurons — the VC neurons — form axonal branches at the vulva that travel a short way from the ventral nerve cord along the vulval epithelium before stopping. In the new study, Colavita and Tessier-Lavigne found that mutations in a particular gene, bam-2, cause the branches to overshoot so that they continue to extend across the vulval midline. bam-2 is expressed in a number of cells, including the vulval VulF cell, but not in the VC neurons.

The phenotype of bam-2 mutants could be rescued by expression of bam-2 in the VulF cell but not by expression in the VC neurons. The cytoplasmic domain of BAM-2 seems not to be needed for its branch-termination role, as a truncated bam-2 gene that lacked this domain could also rescue the phenotype. The sequence of the BAM-2 protein indicates that it is a cell-surface protein and is related to the neurexin family, members of which have been implicated in synaptogenesis.

Ectopic expression of bam-2 in the VC neurons of bam-2-null worms caused an interesting additional phenotype: in 43% of cases, one branch fascicle failed to form completely. Ectopic expression in a wild-type background did not have this effect. The authors propose that BAM-2 acts as a positive signal that attracts axon branches to the appropriate termination point: in the wild type, the normally expressed BAM-2 on the VulF cell overrides the effects of the transgene, but in the bam-2-null worms, ectopic expression in the neurons themselves interferes with branch extension.

The results of the study support the proposal that BAM-2 acts as a branch-termination signal for the VC axons. Surprisingly, it does not seem to influence termination of the primary axons; rather, it acts only on their branches. It seems likely that BAM-2 on the VulF cell acts as a ligand for a receptor that is localized to the VC axonal branches.