Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive, vibration-sensing neurons are associated with Meissner’s corpuscles in the skin. In the present study, we found that USH2A, a transmembrane protein with a very large extracellular domain, was found in terminal Schwann cells within Meissner’s corpuscles. Pathogenic USH2A mutations cause Usher’s syndrome, associated with hearing loss and visual impairment. We show that patients with biallelic pathogenic USH2A mutations also have clear and specific impairments in vibrotactile touch perception, as do mutant mice lacking USH2A. Forepaw rapidly adapting mechanoreceptors innervating Meissner’s corpuscles, recorded from Ush2a−/− mice, showed large reductions in vibration sensitivity. However, the USH2A protein was not found in sensory neurons. Thus, loss of USH2A in corpuscular end-organs reduced mechanoreceptor sensitivity as well as vibration perception. Thus, a tether-like protein is required to facilitate detection of small-amplitude vibrations essential for the perception of fine-grained tactile surfaces.
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Electrophysiological data were acquired with specialized software packages that are not accessible to nonspecialized users. Thus, the raw data files for this manuscript are available upon request.
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We thank M. Braunschweig and H. Thränhardt for technical assistance, T. Li (National Institutes of Health) for providing us with Ush2a−/− mice, B. Purfürst for electron microscopy, M. Navarro for assistance with patient recruitment and A. Udhayachandran for advice. The present study was funded by grants from the Deutsche Forschungsgemeinshaft (grant nos. SFB665-B6 to G.R.L., SFB1315 to J.F.A.P. and SFB1158-A01 to S.G.L.) and grants from the European Research Council (grant nos. 789128 to G.R.L. and ERC-2015-CoG-682422 to J.F.A.P.). Additional funding was from the Institute of Health Carlos III (Spanish Ministry of Science and Innovation, grant no. FIS PI16/00539 to J.M.). We thank U. Müller for critical comments on the manuscript.
The authors declare no competing interests.
Peer review information Nature Neuroscience thanks Victoria Abraira, Daniel Huber and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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a, Hit and False alarm lick rates for Ush2a+/+ and b, Ush2a-/- mice during training. Ush2a+/+ and Ush2a-/- mice learned to report 5Hz 60mN forepaw vibration after 4 days (Hit vs False lick rates within each genotype: ***P < 0.001; two-way repeated-measures ANOVA with Bonferroni post-hoc analysis. Ush2a+/+: F(6,60) = 4.486, P=0.006. Ush2a-/-: F(6,48) = 3.698,P=0.004). Light colour lines indicate individual mice, bold lines population mean. c, Perceptual sensitivity (d’) measurements indicate increasing sensitivity during training in both Ush2a+/+ and Ush2a-/- mice. Plot shows max and min values, box shows 1st, 2nd (median) and 3rd quartile values. d, Perceptual thresholds of Ush2a+/+ mice to 5Hz stimuli. Ush2a+/+ mice reported 5Hz stimuli ≥12mN, as shown by significantly higher Hit vs False Alarm lick rates ≥12mN (Hit vs False: Two-way repeated measures ANOVA F(5,30) = 16.52, P=0.0005, asterisk indicates Bonferroni post-hoc analyses ***P < 0.001. e, Ush2a-/- mice reported 5Hz vibration stimuli ≥24mN (Hit vs False: two-way repeated-measures ANOVA F(6,24) = 16.52, P<0.0001, asterisk indicates Bonferroni post-hoc analyses ***P < 0.001. f, Mean first lick latencies during hit trials of Ush2a-/- mice were longer at 36mN 5Hz vibration; Two-way repeated-measures ANOVA F(6,63) = 2.306, P=0.045 asterisk indicates Bonferroni post-hoc analysis *P < 0.05. g, Hit and False licking rates during 25Hz vibration detection task in Ush2a+/+ and Ush2a-/- mice. Dots show data from individual mice, horizontal lines show mean. h, Hit and False licking rates of mice during 100Hz vibration detection task in Ush2a+/+ and Ush2a-/- mice. i, Mice trained on the vibration detection did not respond to any sound generated by the vibration stimulus when the Piezo device placed 5mm below the forepaw (paired two-tailed t-tests, Ush2a+/+ P=0.97; Ush2a-/- P=0.17). Data = mean ± s.e.m. n = 11 mice. Filled dot shows hit rates, open dot shows false alarm lick rates.
Extended Data Fig. 2 Ush2a-/- mice have a mild hearing deficit in a paired-pulse inhibition behavioral task.
a, Response amplitudes (in arbitrary units) of Ush2a+/+ (n=10) and Ush2a-/- (n=9) mice to 20-40ms auditory tones of different amplitudes did not differ (Two-way repeated-measures ANOVA analysis F(1,18)=2.937, P=0.10). b, Lower amplitude tones reduced the startle response when given 200ms before the startling 129dB tone in both Ush2a+/+ (n=10) and Ush2a-/- (n=9) mice, however the amplitude of the response was significantly lower in Ush2a-/- mice compared to Ush2a+/+ mice at 73dB and 81bD pre-pulse tones; two-way repeated-measures ANOVA F(1,18)=2.711, P=0.006, asterisks indicate Bonferroni post-hoc analyses *P < 0.01. Data = mean ± s.e.m.
a, USH2A (green) and NF200 (red) immunolabelling of dorsal root ganglia neurons. a’ USH2A channel only. a’’ NF200 channel only. A’’’ RNA scope probe for Ush2a mRNA shows no labelling in the DRG (green) a second probe for NF200 mRNA (red) shows large sensory neurons labeled. The Ush2a RNA labels Meissner corpuscle cells in the skin (green). b NF200 (red), and S100 (cyan) immunolabelling of Meissner corpuscles in the sectioned paw glabrous skin. b’ USH2A channel. b’’ NF200 channel. b’’’ S100 . c, USH2A (green) and NF200 (red) immunolabelling of deep nerve branches in whole mounted paw skin show an absence of USH2A in nerve bundles. c’ USH2A channel only. c’’ NF200 channel. d, USH2A (green) and NF200 (red) immunolabelling of Meissner corpuscles in the sectioned paw glabrous skin from an Ush2a-/- mouse show an absence of USH2A labelling. d’ USH2A channel only. d’’ NF200 channel only.
Extended Data Fig. 4 Ex vivo forepaw and hind paw skin nerve preparation recordings from cutaneous RAM Aβ-fibers.
a, The proportion of forepaw RAMs responding to 5Hz (top) and 50Hz (bottom) vibration stimuli in Ush2a+/+ (n = 11 from 5 mice) and Ush2a-/- mice (n = 10 from 4 mice). b, Ush2a-/- forepaw RAMs (n = 10) were less responsive to 10Hz, two-way repeated-measures ANOVA F(1,12) = 8.277, P=0.014 and c, 50Hz vibration, two-way repeated-measures ANOVA F(1,19) = 8.155, P=0.010 compared to RAMs in Ush2a+/+ mice (n = 11) asterisks indicate Bonferroni post-hoc analyses **P < 0.01, *** P < 0.001. d, Number of spikes per sinusoid decreases with stimulus amplitude in Ush2a+/+ forepaw RAMs (n = 11) compared to Ush2a-/- (n = 10). e. Number of spikes per sinusoid for vibration stimuli (5-50 Hz) was lower in Ush2a-/- forepaw RAMs (n = 10) compared to Ush2a+/+ (n = 11). f, Hind paw glabrous Aβ-fiber RAMs recorded from Ush2a-/- mice (n = 14 from 4 mice) were less responsive to 5Hz, two-way repeated-measures ANOVA F(1,25) = 8.028, P=0.009) (left asterisks indicate Bonferroni post-hoc analyses *,**P < 0.05, 0.01. g, but not 50Hz vibration compared to Ush2a+/+ mice (n = 13 from 4 mice), two-way repeated-measures ANOVA F(1,24) = 2.101, P=0.16. h, Hind paw glabrous RAM responses to different ramp velocities were significantly lower in Ush2a-/- mice (n = 10) compared to Ush2a+/+ mice (n = 11), two-way repeated-measures ANOVA. F(1,43) = 8.112, P=0.007, asterisks indicate Bonferroni post-hoc analyses *P < 0.05. i, Forepaw Aβ-fiber RAMs (n = 11 neurons from 5 mice) were significantly more sensitive to 5Hz and, j, 50Hz vibration compared to hind paw RAMs in Ush2a+/+ mice two-way repeated-measures ANOVA. 5Hz: F(1,21)=40.26, P<0.0001; 50Hz: F(1,16)=6.970, P=0.018; asterisks indicate Bonferroni post-hoc analyses *,**,***P < 0.05, 0.01, 0.001 (n = 13, 4 mice). k, Aβ-fiber SAM responses to 5Hz vibration were significantly higher in the forepaw (n = 12) compared to hindpaw (n = 14) in Ush2a+/+ mice, two-way repeated-measures ANOVA F(1,21) = 8.210, P=0.009) Data = mean ± s.e.m.
a, Whole mount USH2A (green) and S100 immunolabelling of a hair follicle with lanceolate endings in the hind paw hairy skin. a’ USH2A channel only. a’’ S100 channel only. Scale bars 25µm. b, Wholemount USH2A (green) and S100 (red) immunolabelling of a hair follicle with circumferential (circ) endings showing USH2A expression in the hind paw hairy skin. b’ USH2A channel only. b’’ S100 channel only. Scale bars 25µm. c, Wholemount USH2A (green) and S100 (red) immunolabelling of a hair follicle with circumferential endings that is USH2A-negative in the hind paw hairy skin. c’ USH2A channel only. c’’ NF200 channel only. Scale bars 25µm. d, Whole mount USH2A (green) and CK20 (red: marker of Merkel cells) immunolabelling of Guard hair in the back hairy skin with surrounding Merkel cell complex. Note the lack of overlap between USH2A and CK20 immunolabelling. d’ USH2A channel only. d’’ S100 channel only. Scale bars 50µm. e, USH2A (green) and S100 (red) immunolabelling of D-hairs in sectioned glabrous hind paw skin, showing absence of USH2A staining in D-hairs. e’ USH2A channel only. e’’ S100 channel only. All scale bars = 50µm.
Extended Data Fig. 6 Aβ-fiber SAMs and Aδ-fiber D-hairs have normal mechanosensitivity in Ush2a-/- mice.
a, Example traces of single SAMs recorded from Ush2a+/+ (top) and Ush2a-/- (bottom) mice firing in response to the 5Hz vibration protocol. b, SAMs recorded from Ush2a+/+ (n=10 from 4 mice) and Ush2a-/- (n=11 from 4 mice) mice show comparable sensitivity to 25Hz and c, 50Hz vibration (Ush2a+/+ n=10; Ush2a-/- n=11); Two-way repeated-measures ANOVA F(1,19)=0.3011, P=0.59. d, Aδ-fiber D-hairs recorded from the hairy hind paw skin and glabrous hind paw skin in Ush2a+/+ (n=9 from 6 mice) and Ush2a-/- (n=11 from 6 mice) mice showed comparable sensitivity to 25Hz and e, 50Hz vibration (Two-way repeated-measures ANOVA 25Hz: F (1,19)=0.00006, P=0.99. 50Hz: F(1,19) > 0.1, P=0.68). f, D-hair vibration frequency tuning was not significantly different in Ush2a+/+ and Ush2a-/- mice (Ush2a+/+ n=9; Ush2a-/- n=11. Two-way repeated-measures ANOVA F(1,17) = 0.0001, P=0.99). All data = mean ± s.e.m.
Extended Data Fig. 7 Warm and cool detection by forepaw thermoreceptors is not impaired in Ush2a-/- mice.
a, The percentages of forepaw thermoreceptive C- and A-fibers classified by their response to different stimuli in Ush2a+/+ and Ush2a-/- mice (n=48 from 6 mice). C-MH = C-mechanoheat; C-MHC = C-mechanoheatcold; C-MC = C-mechanocold; C-C = C-cold; A-MC = A-mechanocold. b, Firing rates of cool-sensitive afferents recorded in Ush2a+/+ and Ush2a-/- mice during a 32-12 °C ramp (temperature change = 1 °C/second) was not statistically different (two-way repeated-measures ANOVA F(1,31)=0.0013, P=0.97). c, Similarly, firing rates of heat-sensitive thermoreceptors during a 32-48 °C ramp did not differ between Ush2a+/+ and Ush2a-/- mice (two-way repeated-measures ANOVA F(1,20)=0.2716, P=0.61). Data = mean ± s.e.m.
Extended Data Fig. 8 Tibial nerve sensory neurons and hind paw skin touch end-organs in Ush2a-/- mice show no anatomical defects.
a, electron micrographs of the tibial nerve from an Ush2a+/+ mouse. Myelinated fibers have thick grey circumference; Remak bundles of C-fibers lack myelination. a’, Representative electron micrograph of the tibial nerve from an Ush2a-/- mouse. Scale bars = 2µm. b, Mean numbers of A and C-fibers in the tibial nerves of Ush2a+/+ (n = 3) and Ush2a-/- mice (n = 3) did not appear to differ. Data quantified from EM images. c, Myelin thickness of tibial axons did not differ between Ush2a+/+ (n = 3) and Ush2a-/- mice (n = 3). d, Example S100 (green) and NF200 (red) labelling of Meissner corpuscles in the glabrous hind paw skin of an Ush2a+/+ mouse and e, an Ush2a-/- mouse showed no morphological deficits. Scale bars = 50µm. f, Mean number of fibers innervating each Meissner corpuscle did not differ between Ush2a+/+ (n = 5 mice) and Ush2a-/- mice (n = 5 mice: P < 0.05; two-way ANOVA, F(1,16)=0.0, P=0.99), whisker indicates max and min values, box indicates 1st 2nd (median) and 3rd quartiles. g, Immunolabelling S100 (green) and NF200 (red) labels hair follicles in the skin of an Ush2a+/+ mouse. Scale bar = 25µm. h, S100 (green) and NF200 (red) labelling hair follicles in the skin of an Ush2a-/- mouse showed no obvious deficits. Scale bar = 25µm. i, Hair bulb thickness of awl/zigzag hairs and Guard hairs did not differ between Ush2a+/+ (n = 5) and Ush2a-/- mice (n = 5), unpaired two-tailed t-tests, P=0.64 and P=0.77. Similarly, j, number of terminal Schwann cells per hair follicle (Ush2a+/+ n = 5, Ush2a-/- mice n = 5. P=0.30 and P=0.93.) k, mean terminal Schwann cell soma size (Ush2a+/+ n = 5, Ush2a-/- mice n = 5. P=0.57 and P=0.28) l, and branch lengths did not differ between Ush2a+/+ (n = 5) and Ush2a-/- mice (n = 5), unpaired two-tailed t-tests, P=0.65 and P=0.39). Data = mean ± s.e.m.
Extended Data Fig. 9 Impaired forepaw RAM mechanosensitivity underlies 25Hz vibration perceptual deficits in Ush2a-/- mice.
a, Box and whisker plot of median first lick latencies of Ush2a+/+ (n=6) and Ush2a-/- (n=5) mice at 5Hz, 25Hz and 100Hz frequency vibration, whisker indicates max and min values, box indicates 1st 2nd (median) and 3rd quartiles. b PSTHs of first lick responses to 25Hz 12mN vibration stimuli from all behaving Ush2a+/+ and Ush2a-/- trials. Peak first lick Hit responses above False lick rates indicate first responses of mice 25Hz stimuli. Ush2a-/- mice did not detect this stimulus c Spike timing raster plots of individual forepaw RAMs and SAMs recorded in response to the first 20 cycles of a 25Hz vibration stimulus in the ex vivo forepaw skin nerve preparation of Ush2a+/+ and Ush2a-/- mice. Each row represents one trial from a single afferent 1-3 trials per recording (left Ush2a+/+ RAM n = 4/11, SAM 2/10 afferents; right Ush2a-/- RAM n = 1/10, SAM 1/11 afferents). d, PSTHs of mean first lick responses to 60mN 25Hz vibration stimuli from all behaving Ush2a+/+ and Ush2a-/-, both genotypes detected this stimulus. e, Spike timings of individual RAMs and SAMs recorded in the ex vivo forepaw skin nerve preparation in Ush2a+/+ and Ush2a-/- mice in response to the first 20 cycles of 60mN 25Hz stimuli (left Ush2a+/+ RAM n = 10/11, SAM n = 10/10; right Ush2a-/- RAM n = 8/10, SAM n = 10/11). Data = mean ± s.e.m.
a, Force measurement system mounted in series with the Piezo actuator was used to deliver vibration stimuli to the ex vivo preparation. The displacement of the probe was measured and compared with the measured force for the same output voltage when used in the ex vivo preparation. This configuration was used to apply calibrated vibration stimuli to skin mechanoreceptors.
Supplementary Tables 1–3.
Animated z-projection of the Meissner’s corpuscle pictured in Fig. 2a.
Animated z-axis projections of a single Meissner’s corpuscle labeled for USH2A (green), S100B (magenta) and NF200 sensory axons (blue).
Animated z-axis projections of a single Meissner’s corpuscle labeled for USH2A (green), S100B (magenta) and NF200 sensory axons (blue).
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Schwaller, F., Bégay, V., García-García, G. et al. USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans. Nat Neurosci 24, 74–81 (2021). https://doi.org/10.1038/s41593-020-00751-y