Neurons in the developing brain send out axons that must navigate a complex meshwork of cells to specific layers called laminae. Joshua Shanes and colleagues now show us how these axons reach their destination with precision. In the 6 September issue of Cell, they demonstrate that Sidekick-1 and -2, transmembrane proteins in the immunoglobulin superfamily, guide axon terminals to specific laminae. This confocal image shows concentrated expression of Sidekick-2 (green) near the synaptic cleft, sandwiched between presynaptic terminals (red) and the postsynaptic apparatus (blue) in the chicken retina. Expression of Sidekick-1 in presynaptic cells targets axons to laminae expressing Sidekick-1. A similar pattern occurs between Sidekick-2-expressing presynaptic cells and Sidekick-2 laminae. The authors went on to demonstrate that each Sidekick binds to its own kind in vitro, and that in the retina their expression patterns do not overlap. Ectopic expression of either protein in Sidekick-negative cells redirects axon terminals to laminae expressing the same Sidekick. The data indicate that expression of Sidekicks in pre- and postsynaptic neurons directs formation of the synapse.
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Stebbins, M. Ain't that a Sidekick in the head. Nat Med 8, 1085 (2002). https://doi.org/10.1038/nm1002-1085