[
Neuron,
1996]
The idea of chemoattraction as a guiding mechanism for growing axons was originally suggested by Ramon y Cajal as a result of earlier work on leucocytes. Discussing the ventral navigation of commissural axons toward the midline floor plate in the developing spinal cord, he wrote: ...The oblique direction assumed by these axons would be explained if chemoattractants produced by the ventral half of the neuroepithelium were stronger than those produced by the rest of the epithelium...a sufficiently extended period of chemoattractant secretion by the floor plate could explain the relatively long period of time over which the ventral commissure is formed". Chemoattraction is well established at the molecular level in leucocyte biology, but good evidence was lacking in the vertebrate nervous system until collagen gels were used to assay for chemoattractants, allowing the purification and cloning of netrins. The homology then revealed between netrins and UNC-6, a laminin-related protein required for circumferential dorsal and ventral migrations of axons in the body wall of Caenorhabditis elegans, further suggested that netrins may provide highly conserved midline guidance cues for axons, operating in organisms ranging from nematode worms to higher vertebrates. This appealing view is now amply confirmed with an impressive group of studies using worms, flies, and rodents to analyze neural development in the face of netrin loss- and gain-of-function, and the story has simultaneously taken a significant step forward with the identification of the structure and function of netrin receptors.