UNC-6 (Netrin) Orients the Invasive Membrane of the Anchor Cell in C. elegans

Despite profound importance in development and cancer, the extracellular cues that target cell invasions through basement membrane barriers remain poorly understood 1. A central obstacle has been the difficulty of studying the interactions between invading cells and basement membranes in vivo 2,3. Using the genetically and visually tractable model of C. elegans anchor cell (AC) invasion, we show that unc-6 (netrin) signaling, a pathway not previously implicated in controlling cell invasion in vivo, is a key regulator of this process. Site of action studies reveal that prior to invasion localized UNC-6 secretion directs its receptor, UNC-40, to the AC’s plasma membrane in contact with the basement membrane. There, UNC-40 polarizes a specialized invasive membrane domain through the enrichment of actin regulators, F-actin and phosphatidylinositol 4,5-bisphosphate. Cell ablation experiments indicate that UNC-6 promotes the formation of invasive protrusions from the AC that break down the basement membrane in response to a subsequent vulval cue. Together, these results characterize an invasive membrane domain in vivo, and reveal a novel role for netrin in polarizing this domain towards its basement membrane target.