Axonal guidance and its underlying mechanisms have been the subject of intense study for decades. In Drosophila, many axon guidance molecules have been identified and their mutant phenotypes studied. However, less attention has been directed towards the functional consequences of developmental defects in guidance and wiring. Here, Hermann Aberle and colleagues characterise the loss- and gain-of-function phenotypes of sidestep (side), with a particular focus on how the defects caused by altered Side levels impact on locomotor behaviour in the late larva. Side is known to act as an attractant for motor axons – promoting growth towards and innervation of the body wall muscles. The authors show that side mutants display axon guidance defects that persist to late larval stages and are highly variable – between individuals, between hemisegments of an individual, and across left and right sides of the animal. Some muscles lack neuromuscular junctions, while others are hyper-innervated. Overexpression of side also induces guidance defects – most notably, a loss of innervation to the dorsal-most muscles. Behaviourally, both genetic conditions result in severe locomotor defects: the peristaltic tail-to-head contractions are largely preserved, but the larvae crawl slowly, displaying unusual body arching, and head and tail lifting motions. These analyses connect early miswiring patterns to late behavioural phenotypes, and underscore the crucial importance of precise axon guidance during development.
