Dendrite self-avoidance is controlled by Dscam and counterbalances attractive guidance signaling in Drosophila

Dendrites distinguish between sister branches and those of other cells. Self-recognition can often lead to repulsion, a process termed "self-avoidance." Here I demonstrate that dendrite self-avoidance in Drosophila da sensory neurons requires cell recognition molecules encoded by the Dscam locus. The Drosophila Dscam locus is highly diversified through alternative splicing of its ectodomain, generating isoforms with up to 19,008 distinct extracellular sequences, the majority of which exhibit preferential homophilic binding interactions. We present data indicating that interactions between identical Dscam isoforms on the cell surface underlie self-recognition, while the cytoplasmic tail converts this recognition to dendrite repulsion. Although a single isoform is sufficient to support self-avoidance within a single arbor, isoform diversity allows neighboring neurons to express largely dissimilar complements of Dscam and thus avoid inappropriate interactions. By reducing the number of isoforms potentially encoded by the Dscam locus and examining the consequences on self-avoidance, we show that anything less than thousands of potential ectodomains leads to inappropriate interactions between neighboring da neurons and interferes with their ability to selectively self-avoid.;In addition to branch overlaps, sister dendrites lacking Dscam show ectopic accumulation, bundling, and fasciculation, leading to the hypothesis that Dscam normally counterbalances responses to extrinsic signals or adhesive cues. We show here that one such cue in Drosophila sensory neurons corresponds to Netrin-Frazzled signaling. Dendrite accumulations occur at normal sensory dendrite targets that express Netrin-B, and that both Netrin-B and the attractive Netrin receptor Frazzled are required for normal targeting of dendrites. Mutations in Frazzled abolish the accumulation phenotype in Dscam mutant neurons and mutations in both Frazzled and Dscam results in severe deficits in dendritic territory coverage. Consistent with separable roles for Frazzled and Dscam, Netrin misexpression is sufficient to induce ectopic Frazzled-dependent, Dscam-independent dendrite targeting. Thus, self-avoidance counterbalances the actions of defined extrinsic signals whose action would otherwise favor sister neurite accumulation. We also demonstrate that conserved elements of Frazzled-mediated guidance pathways in other contexts, including the P3 motif in the cytoplasmic tail of Frazzled and the GEF Trio are involved in guiding dendrites in response to Netrin. These studies have revealed key molecular mechanisms involved in dendrite self-avoidance and guidance, and have established a model system for further examinations of the signaling pathways underlying these phenomena.