Lgr4 and Lgr5 trigger cytoneme formation

Leucine-rich G-protein-coupled receptors (Lgrs) have been shown to identify many stem and cancer cell populations in mammals. However, despite their common use as stem cell markers, little is known about their physiological function. On page 1230, Marc Caron and colleagues show that Lgr4 and Lgr5 can direct cells to form ultra-long filopodium-like protrusions that bear morphological and biochemical similarities to cytonemes, structures first described in sea urchins and shown to direct morphogen gradients in Drosophila. When the authors blocked the rapid internalisation of Lgr5 or overexpressed Lgr4 at the plasma membrane, cells formed long membrane protrusions, which, except for their length, bore the characteristics of filopodia – they were rich in polymerised actin and contained VASP, fascin and myosin X. In addition, the protrusions were abolished upon treatment with the actin polymerisation inhibitor cytochalasin B, and were restored when the drug was removed. As cytonemes are well-known cell signalling compartments, the authors then investigated their role in G-protein-coupled receptor signalling. Indeed, upon activation of the β-2 adrenergic receptor, its adaptor protein β-arrestin-2 was recruited into Lgr5-induced cytonemes by myosin X, demonstrating their potential role as a platform for the delivery of signalling effectors. Thus, the findings presented here not only uncover a function of Lgr5 and Lgr4, but also provide a novel mechanism for how stem cells and cancer cells could communicate with their nonclonal environment.