From tags to RAGS: Chemoaffinity finally has receptors and ligands

In the early 1940s, Roger Sperry cut the optic nerve of a newt, rotated the detached eye 180 ° in its orbit, and assayed the visuomotor behavior of the animal after its nerve had regenerated. The newts, and in subsequent studies, frogs, behaved as if their visual world were back to front and upside down: when a lure was presented in front of them, =they wheeled rapidly to the rear instead of striking forward," and when the lure was presented above, =the animals struck downward in front of them and got a mouthful of mud and moss ~ (Sperry, 1944). This experiment led him to propose that topographic nerve connections between the retina and its main central target, the optic tec-tum, are governed by sets of complementary "cytochemi. cal tags." This novel idea contrasted with the prevailing views of the time and stands as one of the most profound insights in developmental neurobiology. Sperry subsequently demonstrated the existence of topographic maps and proposed a mechanism for their formation (Sperry, 1963). Now, more than 50 years after Sperry's eye rotation experiments, the search for these molecules is beginning to end with the work presented in two papers in a recent issue of Cell (Cheng et al., 1995; Drescher et al., 1995). Until Sperry's experiments, it was thought that the nervous system formed appropriate connections using electrical resonance or mechanical guidance (Weiss, 1955). According to the resonance hypothesis, axons that connected appropriately produced rewarding patterns of behaviors that somehow resonated with these connections, while inappropriate neural projections that produced aberrant behaviors were silenced or eliminated. This view was crushed by Sperry's experiment because "the stupid frogs never learned," as Sperry laughingly would tell his students. They lived the rest of their lives jumping backwards for flies that appeared in front of them. The mechanical view, which also seemed incompatible with Sperry's findings , was that nerve fibers were guided to their targets by morphogenetic factors, such as micromechanical stress lines or grooves in the tissue. Indeed, scratches on synthetic surfaces were shown to be capable of guiding fiber growth in culture (Weiss, 1955). However, Sperry observed that optic nerve fibers regrew in a haphazard way, often following tortuous trajectories, yet they were still able to sort themselves out and home in on their original targets. This observation argued against the idea that nerve fibers were simply channeled into their correct places by …