Dscam diversity is essential for neuronal wiring and self-recognition

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Abstract
The complexity and specificity of neuronal wiring implies the existence of a cellular recognition code that allows neurons to distinguish between one another. The remarkable diversity of the immunoglobulin superfamily protein Dscam (for Down syndrome cell adhesion molecule) may be part of that system. Dscam plays a crucial role in making Drosophila neurons able to distinguish between self and non-self, and is essential to patterning neural circuits. Use of a novel approach to generate mosaic animals shows that Down syndrome cell adhesion molecules (Dscam) diversity plays a crucial role in providing neurons in the Drosophila central nervous system with the ability to distinguish between self and non-self, which is essential to patterning neural circuits. Neurons are thought to use diverse families of cell-surface molecules for cell recognition during circuit assembly. In Drosophila, alternative splicing of the Down syndrome cell adhesion molecule (Dscam) gene potentially generates 38,016 closely related transmembrane proteins of the immunoglobulin superfamily, each comprising one of 19,008 alternative ectodomains linked to one of two alternative transmembrane segments1. These ectodomains show isoform-specific homophilic binding, leading to speculation that Dscam proteins mediate cell recognition2. Genetic studies have established that Dscam is required for neural circuit assembly1,3,4,5,6,7,8,9,10, but the extent to which isoform diversity contributes to this process is not known. Here we provide conclusive evidence that Dscam diversity is essential for circuit assembly. Using homologous recombination, we reduced the entire repertoire of Dscam ectodomains to just a single isoform. Neural circuits in these mutants are severely disorganized. Furthermore, we show that it is crucial for neighbouring neurons to express distinct isoforms, but that the specific identity of the isoforms expressed in an individual neuron is unimportant. We conclude that Dscam diversity provides each neuron with a unique identity by which it can distinguish its own processes from those of other neurons, and that this self-recognition is essential for wiring the Drosophila brain.