By alternative splicing, Drosophila Down syndrome cell adhesion molecule (Dscam1) encodes tens of thousands of proteins required for establishing neural circuits, while Chelicerata encodes a family of ~ 100 shortened Dscam (sDscam) isoforms via alternative promoters. We report that Dscam isoforms interact promiscuously in cis to generate a vast repertoire of combinatorial homophilic recognition specificities in Chelicerata. Specifically, sDscams formed high order cis-multimers without isoform

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... ecificity involving the membrane-proximal fibronectin type III (FNIII) 1-3 and transmembrane (TM) domains and associated specifically in trans via antiparallel self-binding of the first variable immunoglobulin (Ig1) domain. We propose that such sDscam combinatorial homophilic specificity is sufficient to provide each neuron with a unique identity for self/non-self discrimination. In many respects, our results amazingly mirror those reported for the structurally unrelated vertebrate protocadherins (Pcdh) rather than for the closely related fly Dscam1. Thus, our findings blur the distinction between the neuronal self-avoidance of invertebrates and vertebrates and provide insight into the basic principles and evolution of metazoan self-avoidance and self/non-self discrimination.