No sidesteps on a beaten track: motor axons follow a labeled substrate pathway.

The establishment of synaptic connections between motor neurons and muscle fibers is essential for controlled body movements in any higher organism. The wiring of the neuromuscular system in Drosophila serves as a model system for the identification of key regulatory proteins that control axon guidance and target recognition. Sidestep (Side) is a transmembrane protein of the immunoglobulin superfamily and plays a pivotal role in the coordination of motor axonal guidance decisions, as it functions as a target-derived attractant. Side, however, is expressed in a highly dynamic pattern during embryogenesis, making it difficult to deduce its precise function. We have recently shown that the expression of Side strongly correlates with the actual position of motor axonal growth cones. Motor axons seem to recognize and follow Side-positive surfaces until they reach their target fields. The motor neuronal protein Beaten path Ia (Beat) is required to detect Side. In beat mutant embryos, motor axons are no longer attracted to Side-expressing tissues. In addition, Beat and Side interact biochemically, forming heterophilic adhesion complexes in vitro. Here, I discuss the model that preferential adhesion of Beat-expressing growth cones to Side-labeled substrates could be a powerful mechanism to guide motor axons.