TENM4 is an essential transduction component for touch and pain
Gentle touch is conveyed to the brain by fast-conducting sensory fibers. Mechanosensitive ion channels at the terminals of these neurons are thought to be gated by extracellular tethers that transmit force from the surrounding matrix to the channel complex, but the molecular identity of such tethers has remained unknown. Here, we identify Teneurin-4 (TENM4) as an essential extracellular linker protein for mechanotransduction in mechanoreceptors. Sensory neuron-specific deletion of Tenm4 in mice caused profound touch insensitivity, while acute and reversible proteolytic disassembly of TENM4 at sensory endings confirmed its direct role in force transduction. Ultrastructural analyses revealed TENM4 localization to filamentous structures at the neurite-laminin interface, defining it as a structural component of the mechanosensory tether. These findings identify TENM4 as a core element of fast somatic sensation and provide molecular insight into how extracellular forces are coupled to ion channel activation.