Dendrites use mechanosensitive channels to proofread ligand-mediated neurite extension during morphogenesis

Ligand-receptor interactions guide axon navigation and dendrite arborization. Mechanical forces also influence guidance choices. However, the nature of such mechanical stimulations, the mechanosensor 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 Ca²⁺ transients in growing dendritic filopodia via activation of L-type voltage-gated Ca²⁺ channels. Anchoring of filopodia by dendrite ligand-receptor complexes is required for the mechanical activation of DEG/ENaC channels. Therefore, mechanosensitive channels serve as a checkpoint for appropriate chemoaffinity by activating Ca²⁺ transients required for neurite growth.