TENM4 IS A MAJOR COMPONENT OF TETHERS REQUIRED FOR TOUCH

Our ability to perceive touch depends on specialized mechanosensory neurons in the skin that detect nanometer-scale mechanical displacements and convert them into electrical signals. Key molecular components of this mechanotransduction process have recently been identified, including the mechanosensitive ion channels Piezo2 and Elkin1. However, the precise mechanisms by which mechanical forces gate these channels remain poorly understood. We hypothesize that their activation requires mechanical coupling to the extracellular matrix (ECM) via specialized protein tethers. In sensory neurons, these tethers appear as electron-dense extracellular filaments, bridging the gap between neurites and the matrix. In our search for the molecular identity of these structures, we have narrowed the list of candidates to a small group of ECM-associated proteins, with the transmembrane protein TENM4 emerging as the most compelling candidate. We have previously demonstrated that TENM4 is critically required for normal touch sensation in vivo, possibly by participating in the formation of these tethers through interactions with other ECM proteins in the skin. In the present study, we show that TENM4 localizes specifically to the tether structures in sensory neurons, as revealed by immunogold labeling combined with transmission electron microscopy. Additionally, using affinity purification and proximity biotinylation, we identified multiple ECM proteins as potential TENM4 interactors in the skin. These findings support a model in which TENM4 plays a central role in tether assembly and function by linking mechanosensitive ion channels to the ECM, thereby enabling efficient force transmission during tactile stimulation.