The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals1. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive2. Piezo2 is a rapidly adapting, mechanically activated ion channel expressed in a subset of sensory neurons of the dorsal root ganglion and in cutaneous mechanoreceptors known as Merkel-cell–neurite complexes3,4. It has been demonstrated that Merkel cells have a role in vertebrate mechanosensation using Piezo2, particularly in shaping the type of current sent by the innervating sensory neuron4,5,6; however, major aspects of touch sensation remain intact without Merkel cell activity4,7. Here we show that mice lacking Piezo2 in both adult sensory neurons and Merkel cells exhibit a profound loss of touch sensation. We precisely localize Piezo2 to the peripheral endings of a broad range of low-threshold mechanoreceptors that innervate both hairy and glabrous skin. Most rapidly adapting, mechanically activated currents in dorsal root ganglion neuronal cultures are absent in Piezo2 conditional knockout mice, and ex vivo skin nerve preparation studies show that the mechanosensitivity of low-threshold mechanoreceptors strongly depends on Piezo2. This cellular phenotype correlates with an unprecedented behavioural phenotype: an almost complete deficit in light-touch sensation in multiple behavioural assays, without affecting other somatosensory functions. Our results highlight that a single ion channel that displays rapidly adapting, mechanically activated currents in vitro is responsible for the mechanosensitivity of most low-threshold mechanoreceptor subtypes involved in innocuous touch sensation. Notably, we find that touch and pain sensation are separable, suggesting that as-yet-unknown mechanically activated ion channel(s) must account for noxious (painful) mechanosensation.
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We acknowledge T. Goode for help in behavioural analysis. We also thank R. Moran and T. Johnson for assistance with histology, K. Spencer for imaging analysis and M. Braunschweig for technical assistance. S.S.R. was funded by a pre-doctoral fellowship from the California Institute of Regenerative Medicine. R.A.M. was supported by Clinical Research Fellowship from the Max Delbrück Center (MDC). G.R.L.’s laboratory was supported by senior European Research Council grant (project 294678) and a grant from the Deutsche Forschungsgemeinshaft (SFB958 project A9). A.P. is a Howard Hughes Medical Institute Investigator. This study was partly funded by NIH grant R01 DE022358 to A.P.
The authors declare no competing financial interests.
Extended data figures and tables
Extended Data Figure 1 Mechanically activated currents elicited in cultured DRG neurons from Piezo2WT and Piezo2CKO mice by poking with a blunt probe.
a, Representative traces of rapidly adapting (RA) currents in Piezo2WT (top) and Piezo2CKO (bottom). Piezo2WT DRG neurons show characteristic rapidly adapting currents; a subpopulation can be active with apparent low thresholds (right). Piezo2CKO mice contained a few rapidly adapting type cells but none appeared to be low-threshold mechanoreceptors. b, c, Representative traces of intermediately adapting (IA) and slowly adapting (SA) currents, respectively, with no observable differences between the two genotypes. All data were low-pass filtered off line at 4 kHz. Action potentials were elicited by current injection in all neurons. Piezo2WT: RA, left: 20 μm diameter, 5 μm apparent threshold; RA, right: 28 μm diameter, 1 μm apparent threshold; IA: 23 μm diameter, 6 μm apparent threshold; SA: 20 μm diameter; 2 μm apparent threshold. Piezo2CKO: RA, left: 23 μm diameter, 8 μm apparent threshold; RA, right: none found; IA: 20 μm diameter, 5.5 μm apparent threshold; SA: 30 μm diameter, 8 μm apparent threshold. Lower right shows an example of the probe displacement protocol (stimulus). Results from n = 3 independent experiments.
The smallest soma indentation eliciting a detectable mechanically activated response (apparent threshold) depends, in part, on the incremental distance applied (0.5 μm) and the proportional displacement in relation to the soma diameter. The apparent thresholds of all rapidly adapting responses normalized to soma diameter reveal a wide range of sensitivities of Piezo2WT DRG neurons (black) and the high apparent threshold responses of the remaining rapidly adapting neurons in Piezo2CKO DRG neurons (red). The lowest apparent thresholds are observed only in Piezo2WT. Results from n = 3 independent experiments.
Extended Data Figure 3 Expression of various markers of subpopulations of DRG neurons are similar in Piezo2WT and Piezo2CKO mice.
a, b, Representative images from immunofluorescence of Nefh in DRGs from Piezo2WT (a) or Piezo2CKO (b) mice. c, d, Representative image from immunofluorescence of thymidine hydroxylase (TH) in DRGs from Piezo2WT (c) or Piezo2CKO (d) mice. e, f, Representative image from immunofluorescence of CGRP in DRGs from Piezo2WT (e) or Piezo2CKO (f) mice. All markers stained in green. Scale bars, 100 μm.
a, d, Representative image of immunostaining of Krt8 (green) and Nefh (red) in Merkel-cell–neurite complexes in Piezo2WT (a) and Piezo2CKO (d) glabrous skin. b, e, f, Representative image of immunostaining of S100 (green) and Nefh (red) in circumferential fibres (arrowheads) and lanceolate endings (arrows) in the hair follicle of Piezo2WT (b) and Piezo2CKO dorsal skin (e and f). c, g, Representative image of immunostaining of S100 (green) and Nefh (red) in Meissner’s corpuscles in Piezo2WT (c) and Piezo2CKO (g) glabrous skin. Bg, bulge of the hair follicle; Der, dermis; Epi, epidermis; HS, hair shaft. Scale bars, 20 μm.
a, No change in conduction velocities of Aβ-, Aδ- and C-fibre afferents in Piezo2CKO compared to Piezo2WT (Mann–Whitney test). b, Proportions of receptor types encountered among Aβ, Aδ and C fibres are shown. A-M, Aδ mechanonociceptor; C-M, C mechanonociceptor; C-MH, C mechano/heat receptor, responding both to noxious heat and mechanical stimuli; RAM, rapidly adapting mechanoreceptor; SAM, slowly adapting mechanoreceptor. c, Stimulus response properties of Aδ mechanonociceptors recorded in Piezo2CKO compared to Piezo2WT were not significantly different. d, D-hair receptors recorded from Piezo2CKO displayed stimulus response properties that were indistinguishable from control afferents. e, The stimulus response properties of C fibres in Piezo2CKO were not significantly different from C fibres recorded in control Piezo2WT mice. Data are presented as mean ± s.e.m., repeated measures ANOVA analysis for c–e.
a, Schematic of instrument construction and image of instrument from above. b, Schematic of the instrument from below, with the top cover removed, and photo of tactile transducers underneath the platform. c, Avoidance behaviour of C57BL/6J mice to the mechanically active side. Error bars represent s.e.m., n = 12 mice, 6 males and 6 females. **P < 0.005, ***P < 0.0001, Mann–Whitney non-parametric analysis.
Extended Data Figure 7 Piezo2CKO mice do not show deficits in noxious mechanical or thermal stimuli or in inflammatory pain responses.
a, Threshold for withdrawal response to a ramping protocol of von Frey stimulation from low force to high in Piezo2WT (n = 9) and Piezo2CKO (n = 7) mice. b, Time to response (latency) to application of a 500 g tail clip to the base of the tail in Piezo2WT (n = 6) and Piezo2CKO (n = 7) mice. c, Threshold for response to a Randall–Selitto pinching stimulus to the hind paw in Piezo2WT (n = 5) and Piezo2CKO (n = 7) mice. d, Time to withdrawal of hind paw in response to an infrared light heat source (Hargreaves assay) in Piezo2WT (n = 13) and Piezo2CKO (n = 9) mice. e, Ramping von Frey protocol in baseline (before CFA injection) and 24 h post CFA injection in Piezo2WT (n = 11) and Piezo2CKO (n = 9) mice. f, Ramping von Frey protocol in baseline (before bradykinin injection) and at time points 5, 15 and 30 min post injection in Piezo2WT (n = 6) and Piezo2CKO (n = 6) mice. Error bars represent s.e.m., all experiments performed with at least two separate cohorts of both male and female mice, **P < 0.005, ***P < 0.0001, Mann–Whitney non-parametric analysis.
a, In situ hybridization expression analysis of Piezo1 in DRG neurons relative to Piezo2. Robust expression of Piezo2 but not Piezo1 is observed, and this agrees with previously reported results using qPCR3. b, siRNA for Piezo1 in cultured DRG neurons does not affect the number of mechanically sensitive neurons or the ratio of rapidly, intermediately or slowly adapting currents (number of recorded neurons in each category indicated on top of bar graphs). Data from three independent preparations, not significant by Student’s t-test. Scale bar, 100 μm. KD, knockdown; scr, scrambled.
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Ranade, S., Woo, S., Dubin, A. et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014). https://doi.org/10.1038/nature13980
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