Touch sensation is built upon the ability of sensory neurons to detect and transduce nanometer scale mechanical displacements. The underlying process has been termed mechanotransduction: the high sensitivity and speed of which is enabled by direct gating (opening) of ion channels by mechanical force. Force detection is functionally compartmentalized and only takes place at the peripheral endings of sensory neurons in vivo. Now three molecules were found to be genetically necessary for touch in many sensory neurons, the force gated ion channel PIEZO2 and its modulator STOML3 and the mechanically gated ion channel ELKIN1. However, mechanotransduction complexes in all touch receptors absolutely require tethering to the extracellular matrix for function. Tethering is dependent on large extracellular proteins that are sensitive to site-specific proteases. Here we have for the first time identified the first molecular component of these tethers, a protein called TENM4. To do this we developed technology to acutely and reversibly abolish tethers and other mechanotransducer components. We have used genome engineering to tag tethers and mechanotranduction components in order to visualize and manipulate these proteins at their in vivo sites of action. By engineering de novo cleavage sites for site-specific proteases we rendered tethers newly sensitive to normally ineffective proteases in the skin. We have also now generated mutations into candidate ion channels that dramatically alter biophysical properties to physiologically “mark” function in vivo. Furthermore, the impact of acute and reversible manipulation of mechanotransduction on touch perception has been measured. Our results provide the basis of novel translational efforts to develop drugs to modulate pathological touch as well as pain.
