TENM4 is an essential transduction component for touch and pain

A gentle touch or a painful pinch are relayed to the brain and spinal cord by rapidly conducting myelinated sensory neurons ^1,2 . These sensory neurons possess mechanically activated ion channels like PIEZO2 and ELKIN1 that can be gated by small movements of the substrate ^3–6 . This gating mechanism has been proposed to involve extracellular tether proteins that may transfer force from the matrix to the channel ⁷ , the so-called force from tether model ⁸ . The molecular nature of such tethers has, however, remained elusive. Here we identify the type II membrane protein Teneurin-4 (TENM4) as an essential component for mechanosensory transduction in the vast majority of cutaneous mechanoreceptors, including fast conducting nociceptors. Sensory neuron specific genetic ablation of Tenm4 in mice led to profound touch insensitivity. We devised a strategy to rapidly and reversibly disassemble the TENM4 protein at sensory endings, demonstrating its direct involvement in sensory transduction. TENM4 has been primarily studied in the context of neural development, but here we provide evidence that it transfers force to mechanically activated channels like PIEZO2 and ELKIN1, with which it associates. The identification of TENM4 as an essential component of fast somatic sensation including fast mechanical nociception is a major step towards identifying treatments for sensory disorders including pain.