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Piezo2 channel–Merkel cell signaling modulates the conversion of touch to itch

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Science  04 May 2018:
Vol. 360, Issue 6388, pp. 530-533
DOI: 10.1126/science.aar5703
  • Fig. 1 Alloknesis in aged mice is correlated with a decline in SAІ responses and reduced numbers of touch-dome Merkel cells.

    (A) Alloknesis scores in young (n = 7) and aged (n = 10) mice. (B and C) Scratching responses to intradermal injections of His (B) and CQ (C) in young (n = 8) and aged (n = 8) mice. (D) Firing rates of SAI fibers from young (23 units) and aged (38 units) mice. (E) Touch-dome afferents firing in young and aged mice. Top, ramp-and-hold displacements (50, 100, and 150 mN); bottom, corresponding spike trains. Blue and red lines indicate dynamic and static phases. (F) Proportion of IA responses from young (4.0 ± 2.6%) and aged (56.9 ± 5.1%) mice; n = 7 mice for each group. (G) Firing threshold of SAI fibers from young (25.8 ± 2.5 mN, n = 23) and aged (47.4 ± 6.8 mN, n = 38) mice. (H) Maximum number of spikes in the dynamic phases; n = 23 from young mice (42.0 ± 4.4 counts), n = 38 from aged mice (21.9 ± 2.9 counts). (I) Maximum number of spikes in the static phases; n = 23 from young mice (60.5 ± 7.3 counts), n = 38 from aged mice (26.4 ± 3.5 counts). (J) Confocal images of keratin-8 (K8, red) and neurofilament heavy polypeptide (NFH, green) costaining in a single touch dome. Scale bar, 10 μm. (K) Merkel cell numbers in each touch dome of young (25.1 ± 1.9, n = 30) and aged (14.0 ± 2.0, n = 30) mice. (L) Length of NFH+ fiber innervating touch domes of young (200.2 ± 15.8 μm, n = 30) and aged (178.2.0 ± 16.2 μm, n = 30) mice. Data are presented as mean ± SEM. *P < 0.05, ***P < 0.001, ****P < 0.0001 [Student t test in (A) to (C), (H), (I), (K), and (L); two-way analysis of variance (ANOVA) with Bonferroni post hoc analysis in (D); Fisher’s exact test in (F); Mann-Whitney U test in (G)]; n.s, not significant.

  • Fig. 2 Alloknesis in a mouse model of dry skin is correlated with a decline in SAI responses and reduced numbers of touch-dome Merkel cells.

    (A) Time course of alloknesis in mice treated with AEW (n = 10) or water (n = 10). (B) Confocal images of K8 (red) and NFH (green) costaining in a single touch dome. Scale bar, 10 μm. (C) Merkel cell numbers in touch domes of water-treated (22.6 ± 1.3, n = 26) and AEW-treated (9.6 ± 1.9, n = 26) mice. (D) Length of NFH+ fiber innervating touch domes of water-treated (178.3 ± 15.4 μm, n = 26) and AEW-treated (176.4 ± 13.0 μm, n = 26) mice. (E) Firing traces of SAI afferents in response to mechanical stimulations (50, 100, and 150 mN) in water-treated and AEW-treated mice. (F) Firing rates of SAI fibers from water-treated (n = 17 units) and AEW-treated (n = 19 units) mice. (G) Firing threshold of SAI afferents of water-treated (29.3 ± 2.5 mN, n = 20) and AEW-treated (44.4 ± 8.1 mN, n = 19) mice. (H) Proportion of IA responses of water-treated (5.0 ± 5.0%, n = 5) and AEW-treated (41.7 ± 4.8%, n = 5) groups. (I) Maximum number of spikes in the dynamic phases (water-treated, 28.6 ± 2.5 counts, n = 20; AEW-treated, 13.6 ± 4.3 counts, n = 19). (J) Maximum number of spikes in the static phases (water-treated, 50.0 ± 5.8 counts, n = 20; AEW-treated, 9.5 ± 2.3 counts, n = 19). Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 [two-way ANOVA with Bonferroni post hoc analysis in (A) and (F); Student t test in (C), (D), (I), and (J); Mann-Whitney U test in (G); Fisher’s exact test in (H)].

  • Fig. 3 Chemogenetic activation of Merkel cells is sufficient to modulate alloknesis.

    (A) Alloknesis score in Merkel cell–deficient K14Cre; Atoh1f/f mice (n = 10) and wild-type littermates (n = 10). (B) Traces showing that 300 μM CNO elicited [Ca2+]i responses in tdTomato-positive Merkel cells in hair follicles isolated from Cre+ but not Cre mice. Ionomycin (10 μM) was used as positive control; n = 25 hair follicles from 5 mice. (C) Firings of SAI afferents of AEW-treated Cre and Cre+ mice in response to 100-mN mechanical stimulation in the absence and presence of 300 μM CNO. (D) Firing rates of SAI fibers of AEW-treated Cre (n = 10 units) and Cre+ (n = 5 units) mice in response to increased forces of mechanical stimulation in the absence and presence of 300 μM CNO. (E) Firing threshold of SAI afferents of AEW-treated Cre and Cre+ mice in the absence and presence of 300 μM CNO (Cre n = 10, vehicle control 55.0 ± 12.2 mN, CNO 60.0 ± 10.0 mN; Cre+ n = 5, vehicle control 46.9 ± 3.1 mN, CNO 38.5 ± 11.5 mN). (F) Maximum number of spikes in the dynamic phases (n = 5 Cre mice, vehicle control 10.5 ± 2.2 counts, CNO 12.3 ± 1.6 counts; n = 5 Cre+ mice, vehicle control 7.3 ± 1.0 counts, CNO 8.0 ± 1.8 counts). (G) Maximum number of spikes in the static phases (n = 5 Cre mice, vehicle control 7.7 ± 1.9 counts, CNO 7.4 ± 2.4 counts; n = 5 Cre+ mice, vehicle control 3.7 ± 1.5 counts, CNO 14.2 ± 2.4 counts). (H) Alloknesis of Cre (n = 15) and Cre+ (n = 15) mice treated with vehicle control or CNO. Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 [Student t test in (A) and (F) to (H); two-way ANOVA with Bonferroni post hoc analysis in (D); Mann-Whitney U test in (E)].

  • Fig. 4 Genetic ablation of Piezo2 function in Merkel cells produces alloknesis.

    (A) Alloknesis score in K14Cre; Piezo2f/f mice (n = 10) and wild-type Piezo2f/f littermates (n = 10). (B) Alloknesis score in Atoh1CreERT; Piezo2f/f mice (n = 5) and wild-type Piezo2f/f littermates (n = 4). Data are presented as mean ± SEM. *P < 0.05, **P < 0.01, ****P < 0.0001 (Student t test).

Supplementary Materials

  • Piezo2 channel-Merkel cell signaling modulates the conversion of touch to itch

    Jing Feng, Jialie Luo, Pu Yang, Junhui Du, Brian S. Kim, Hongzhen Hu

    Materials/Methods, Supplementary Text, Tables, Figures, and/or References

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    • Figs. S1 to S11
    • Captions for Movies S1 to S2

    Images, Video, and Other Media

    Movie S1
    Scratching behavior of aged mice in response to mechanical stimulation (0.07 g von Frey hair force). 3 stimuli were delivered to the assigned area (blue circle) at an interval of 10 s.
    Movie S2
    Scratching behavior of young mice in response to mechanical stimulation (0.07 g von Frey hair force). 3 stimuli were delivered to the assigned area (blue circle) at an interval of 10 s.

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