A Network of Cadherin-Mediated Interactions Polarizes Growth Cones to Determine Targeting Specificity

Summary Neuronal growth cones select synaptic partners through interactions with multiple cell surfaces in their environment. Many of these interactions are adhesive, yet it is unclear how growth cones integrate adhesive cues to direct their movements. Here, we examine the mechanisms that enable photoreceptors in the Drosophila visual system to choose synaptic partners. We demonstrate that the classical cadherin, N-cadherin, and an atypical cadherin, Flamingo, act redundantly to instruct the targeting choices made by every photoreceptor axon. These molecules gradually bias the spatial distribution of growth cone filopodia, polarizing each growth cone toward its future synaptic target before direct contact with the target occurs. We demonstrate that these molecules are localized to distinct subcellular domains and create a network of adhesive interactions distributed across many growth cones. Because this network comprises multiple redundant interactions, a complex wiring diagram can be constructed with extraordinary fidelity, suggesting a general principle.