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

Abstract

Specialized mechanosensory end organs within mammalian skin -- hair follicle-associated lanceolate complexes, Meissner corpuscles, and Pacinian corpuscles -- enable our perception of light, dynamic touch. In each of these end organs, fast-conducting mechanically sensitive neurons, called Aβ low-threshold mechanoreceptors (Aβ 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 Aβ LTMRs share a low threshold for mechanical activation, a rapidly adapting (RA) response to force indentation, and high sensitivity to dynamic stimuli. How mechanical stimuli lead to activation of the requisite mechanotransduction channel Piezo2 and Aβ 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 Aβ 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 Aβ 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 Aβ RA-LTMR activation in which axon protrusions anchor Aβ 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.

Caldendrin Is a Repressor of PIEZO2 Channels and Touch Sensation in Mice

“…Multiple classes of MA channels are thought to give rise to the intermediately adapting and slowly adapting currents in DRGNs ( Cho et al, 2002 , 2006 ), but the genes corresponding to these channels remain unknown ( Parpaite et al, 2021 ). However, the MA channel mediating the rapidly adapting currents has been unequivocally identified as PIEZO2 ( Coste et al, 2010 ; Ranade et al, 2014 ) and numerous studies demonstrate a critical role for PIEZO2 in touch sensation and mechanical allodynia ( Ranade et al, 2014 ; Murthy et al, 2018 ; Handler and Ginty, 2021 ; Handler et al, 2023 ). Thus, the tactile hypersensitivity of Cabp1 KO mice could involve enhanced activity of PIEZO2.…”

“…Tactile hypersensitivity could result from the enhanced activity of MA channels such as PIEZO2, in Cabp1 KO DRGNs. Given that multiple channels give rise to MA currents in DRGNs ( Ranade et al, 2014 ; Chesler et al, 2016 ; Parpaite et al, 2021 ; Handler et al, 2023 ), we isolated the effects of caldendrin on PIEZO2 in electrophysiological analyses of neuro2A (N2A) cells transfected with their corresponding cDNAs. To eliminate the contribution of PIEZO1, which is endogenously expressed in N2A cells, we used a clonal N2A cell line in which PIEZO1 was knocked out ( Moroni et al, 2018 ).…”

3D architecture and a bicellular mechanism of touch detection in mechanosensory corpuscle

“…In addition, numerous DCVs are present in avian LCs but have not been reported in mammalian Meissner LCs ( 8 , 28 ). Despite these differences, avian and mammalian corpuscles detect the same stimuli—transient touch and low-frequency vibration—and transmit sensory information via AP firing during the dynamic phase of the stimulus ( 2 , 8 , 9 , 12 – 14 , 19 , 22 , 28 ). Although additional research is needed to evaluate the role of the different structural components, current data suggest that the mechanism of corpuscle function may rely on the interplay between LCs and the afferent terminal via chemical communication and possibly physical interactions via tethers.…”

“…Unlike mammalian corpuscles, avian LCs do not form extensive lamellae, and the afferent terminals in avian LCs have a limited number of protrusions compared to mammalian counterparts. In addition, numerous DCVs are present in avian LCs but have not been reported in mammalian Meissner LCs (8,28). Despite these differences, avian and mammalian corpuscles detect the same stimuli-transient touch and lowfrequency vibration-and transmit sensory information via AP firing during the dynamic phase of the stimulus (2, 8, 9, 12-14, 19, 22, 28).…”

“…Meissner corpuscles endow humans with the remarkable ability to manipulate objects and tools, facilitate sensorimotor control in mice, and enable tactile specialist birds to carry out a multitude of foraging behaviors ( 2 , 8 , 25 – 27 ). While this manuscript was finalized, a preprint study reported the 3D architecture of the mouse Meissner corpuscle by FIB-SEM, which, together with earlier literature, permits a detailed comparison with the avian structure ( 28 ). Both corpuscles contain a stack of LCs innervated by one or two afferents which are mostly, though not exclusively, rapidly adapting.…”