Mechanoreceptor synapses in the brainstem shape the central representation of touch.

Mammals use glabrous (hairless) skin of their hands and feet to navigate and manipulate their environment. Cortical maps of the body surface across species contain disproportionately large numbers of neurons dedicated to glabrous skin sensation, in part reflecting a higher density of mechanoreceptors that innervate these skin regions. Here, we find that disproportionate representation of glabrous skin emerges over postnatal development at the first synapse between peripheral mechanoreceptors and their central targets in the brainstem. Mechanoreceptor synapses undergo developmental refinement that depends on proximity of their terminals to glabrous skin, such that those innervating glabrous skin make synaptic connections that expand their central representation. In mice incapable of sensing gentle touch, mechanoreceptors innervating glabrous skin still make more powerful synapses in the brainstem. We propose that the skin region a mechanoreceptor innervates controls the developmental refinement of its central synapses to shape the representation of touch in the brain.

Activity-dependent development of the body's touch receptors.

We report a role for activity in the development of the primary sensory neurons that detect touch. Genetic deletion of Piezo2, the principal mechanosensitive ion channel in somatosensory neurons, caused profound changes in the formation of mechanosensory end organ structures and altered somatosensory neuron central targeting. Single cell RNA sequencing of Piezo2 conditional mutants revealed changes in gene expression in the sensory neurons activated by light mechanical forces, whereas other neuronal classes were less affected. To further test the role of activity in mechanosensory end organ development, we genetically deleted the voltage-gated sodium channel Nav1.6 (Scn8a) in somatosensory neurons throughout development and found that Scn8a mutants also have disrupted somatosensory neuron morphologies and altered electrophysiological responses to mechanical stimuli. Together, these findings indicate that mechanically evoked neuronal activity acts early in life to shape the maturation of the mechanosensory end organs that underlie our sense of gentle touch.

Three-dimensional reconstructions of mechanosensory end organs suggest a unifying mechanism underlying dynamic, light touch.

Specialized mechanosensory end organs within mammalian skin-hair follicle-associated lanceolate complexes, Meissner corpuscles, and Pacinian corpuscles-enable our perception of light, dynamic touch 1 . In each of these end organs, fast-conducting mechanically sensitive neurons, called Aß low-threshold mechanoreceptors (Aß LTMRs), associate with resident glial cells, known as terminal Schwann cells (TSCs) or lamellar cells, to form complex axon ending structures. Lanceolate-forming and corpuscle-innervating Aß LTMRs share a low threshold for mechanical activation, a rapidly adapting (RA) response to force indentation, and high sensitivity to dynamic stimuli 1-6 . How mechanical stimuli lead to activation of the requisite mechanotransduction channel Piezo2 7-15 and Aß RA-LTMR excitation across the morphologically dissimilar mechanosensory end organ structures is not understood. Here, we report the precise subcellular distribution of Piezo2 and high-resolution, isotropic 3D reconstructions of all three end organs formed by Aß RA-LTMRs determined by large volume enhanced Focused Ion Beam Scanning Electron Microscopy (FIB-SEM) imaging. We found that within each end organ, Piezo2 is enriched along the sensory axon membrane and is minimally or not expressed in TSCs and lamellar cells. We also observed a large number of small cytoplasmic protrusions enriched along the Aß RA-LTMR axon terminals associated with hair follicles, Meissner corpuscles, and Pacinian corpuscles. These axon protrusions reside within close proximity to axonal Piezo2, occasionally contain the channel, and often form adherens junctions with nearby non-neuronal cells. Our findings support a unified model for Aß RA-LTMR activation in which axon protrusions anchor Aß RA-LTMR axon terminals to specialized end organ cells, enabling mechanical stimuli to stretch the axon in hundreds to thousands of sites across an individual end organ and leading to activation of proximal Piezo2 channels and excitation of the neuron.

Three-dimensional reconstructions of mechanosensory end organs suggest a unifying mechanism underlying dynamic, light touch.

Across mammalian skin, structurally complex and diverse mechanosensory end organs respond to mechanical stimuli and enable our perception of dynamic, light touch. How forces act on morphologically dissimilar mechanosensory end organs of the skin to gate the requisite mechanotransduction channel Piezo2 and excite mechanosensory neurons is not understood. Here, we report high-resolution reconstructions of the hair follicle lanceolate complex, Meissner corpuscle, and Pacinian corpuscle and the subcellular distribution of Piezo2 within them. Across all three end organs, Piezo2 is restricted to the sensory axon membrane, including axon protrusions that extend from the axon body. These protrusions, which are numerous and elaborate extensively within the end organs, tether the axon to resident non-neuronal cells via adherens junctions. These findings support a unified model for dynamic touch in which mechanical stimuli stretch hundreds to thousands of axon protrusions across an end organ, opening proximal, axonal Piezo2 channels and exciting the neuron.