Netrins are secreted axon guidance molecules required for commissure formation in a wide range of animal species, including Caenorhabditis elegans, Drosophila melanogaster and mice. They are generally thought to function as chemoattractants, acting at a distance to direct commissural axon growth toward the midline of the central nervous system. We show here, however, that D. melanogaster commissural axons still orient normally and reach the midline even in the complete absence of netrins, though some of them fail to cross the midline. Tethering endogenous netrin to the membrane selectively disrupts its long-range but not short-range activity, yet still allows normal commissure formation. We therefore propose that netrins act in commissural axon guidance as short-range cues that promote midline crossing, not as long-range chemoattractants.
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