Dendrites use mechanosensitive channels to proofread ligand-mediated guidance during morphogenesis

Summary Ligand-receptor interactions guide axon navigation and dendrite arborization. Mechanical forces also influence guidance choices. However, the nature of such mechanical stimulations, the mechanosensors identity and how they interact with guidance receptors are unknown. Here, we demonstrate that mechanosensitive DEG/ENaC channels are required for dendritic arbor morphogenesis in Caenorhabditis elegans . Inhibition of DEG/ENaC channels causes reduced dendritic outgrowth and branching in vivo , a phenotype that is alleviated by overexpression of the mechanosensitive channels PEZO-1/Piezo or YVC1/TrpY1. DEG/ENaCs trigger local Ca 2+ transients in growing dendritic filopodia via activation of L-type voltage-gated Ca 2+ channels. Anchoring of filopodia by guidance ligand/receptor is required for the mechanical activation of DEG/ENaC channels. Therefore, mechanosensitive channels serve as a checkpoint for appropriate chemoaffinity by activating Ca 2+ transients required for neurite growth.