Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Piezo2 is the principal mechanotransduction channel for proprioception


Proprioception, the perception of body and limb position, is mediated by proprioceptors, specialized mechanosensory neurons that convey information about the stretch and tension experienced by muscles, tendons, skin and joints. In mammals, the molecular identity of the stretch-sensitive channel that mediates proprioception is unknown. We found that the mechanically activated nonselective cation channel Piezo2 was expressed in sensory endings of proprioceptors innervating muscle spindles and Golgi tendon organs in mice. Two independent mouse lines that lack Piezo2 in proprioceptive neurons showed severely uncoordinated body movements and abnormal limb positions. Moreover, the mechanosensitivity of parvalbumin-expressing neurons that predominantly mark proprioceptors was dependent on Piezo2 expression in vitro, and the stretch-induced firing of proprioceptors in muscle-nerve recordings was markedly reduced in Piezo2-deficient mice. Together, our results indicate that Piezo2 is the major mechanotransducer of mammalian proprioceptors.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Characterization of mechanically activated currents and Piezo2 expression in proprioceptive neurons.
Figure 2: Characterization of two tissue-specific Piezo2 conditional knockout mice.
Figure 3: Characterization of MA currents in proprioceptive neurons of Piezo2-deficient mice.
Figure 4: Ex vivo recordings of stretch-sensitive muscle afferent activities in two Piezo2 conditional knockout mice.

Similar content being viewed by others


  1. Sherrington, C. On the proprio-ceptive system, especially in its reflex aspect. Brain 29, 467–482 (1907).

    Article  Google Scholar 

  2. Proske, U. & Gandevia, S.C. The proprioceptive senses: their roles in signaling body shape, body position and movement, and muscle force. Physiol. Rev. 92, 1651–1697 (2012).

    Article  CAS  Google Scholar 

  3. Akay, T., Tourtellotte, W.G., Arber, S. & Jessell, T.M. Degradation of mouse locomotor pattern in the absence of proprioceptive sensory feedback. Proc. Natl. Acad. Sci. USA 111, 16877–16882 (2014).

    Article  CAS  Google Scholar 

  4. Bewick, G.S. & Banks, R.W. Mechanotransduction in the muscle spindle. Pflugers Arch. 467, 175–190 (2015).

    Article  CAS  Google Scholar 

  5. Walker, R.G., Willingham, A.T. & Zuker, C.S. A Drosophila mechanosensory transduction channel. Science 287, 2229–2234 (2000).

    Article  CAS  Google Scholar 

  6. Cheng, L.E., Song, W., Looger, L.L., Jan, L.Y. & Jan, Y.N. The role of the TRP channel NompC in Drosophila larval and adult locomotion. Neuron 67, 373–380 (2010).

    Article  CAS  Google Scholar 

  7. Tavernarakis, N., Shreffler, W., Wang, S. & Driscoll, M. unc-8, a DEG/ENaC family member, encodes a subunit of a candidate mechanically gated channel that modulates C. elegans locomotion. Neuron 18, 107–119 (1997).

    Article  CAS  Google Scholar 

  8. Li, W., Feng, Z., Sternberg, P.W. & Xu, X.Z.A. C. elegans stretch receptor neuron revealed by a mechanosensitive TRP channel homologue. Nature 440, 684–687 (2006).

    Article  CAS  Google Scholar 

  9. Suslak, T.J. et al. Piezo is essential for amiloride-sensitive stretch-activated mechanotransduction in larval Drosophila dorsal bipolar dendritic sensory neurons. PLoS ONE 10, e0130969 (2015).

    Article  Google Scholar 

  10. Hunt, C.C., Wilkinson, R.S. & Fukami, Y. Ionic basis of the receptor potential in primary endings of mammalian muscle spindles. J. Gen. Physiol. 71, 683–698 (1978).

    Article  CAS  Google Scholar 

  11. Simon, A., Shenton, F., Hunter, I., Banks, R.W. & Bewick, G.S. Amiloride-sensitive channels are a major contributor to mechanotransduction in mammalian muscle spindles. J. Physiol. (Lond.) 588, 171–185 (2010).

    Article  CAS  Google Scholar 

  12. Coste, B. et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science 330, 55–60 (2010).

    Article  CAS  Google Scholar 

  13. Li, J. et al. Piezo1 integration of vascular architecture with physiological force. Nature 515, 279–282 (2014).

    Article  CAS  Google Scholar 

  14. Maksimovic, S. et al. Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors. Nature 509, 617–621 (2014).

    Article  CAS  Google Scholar 

  15. Ranade, S.S. et al. Piezo1, a mechanically activated ion channel, is required for vascular development in mice. Proc. Natl. Acad. Sci. USA 111, 10347–10352 (2014).

    Article  CAS  Google Scholar 

  16. Ranade, S.S. et al. Piezo2 is the major transducer of mechanical forces for touch sensation in mice. Nature 516, 121–125 (2014).

    Article  CAS  Google Scholar 

  17. Woo, S.H. et al. Piezo2 is required for Merkel-cell mechanotransduction. Nature 509, 622–626 (2014).

    Article  CAS  Google Scholar 

  18. Cahalan, S.M. et al. Piezo1 links mechanical forces to red blood cell volume. eLife 4, e07370 (2015).

    Article  Google Scholar 

  19. de Nooij, J.C., Doobar, S. & Jessell, T.M. Etv1 inactivation reveals proprioceptor subclasses that reflect the level of NT3 expression in muscle targets. Neuron 77, 1055–1068 (2013).

    Article  CAS  Google Scholar 

  20. McCarter, G.C., Reichling, D.B. & Levine, J.D. Mechanical transduction by rat dorsal root ganglion neurons in vitro. Neurosci. Lett. 273, 179–182 (1999).

    Article  CAS  Google Scholar 

  21. Hippenmeyer, S. et al. A developmental switch in the response of DRG neurons to ETS transcription factor signaling. PLoS Biol. 3, e159 (2005).

    Article  Google Scholar 

  22. Madisen, L. et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat. Neurosci. 13, 133–140 (2010).

    Article  CAS  Google Scholar 

  23. Witschi, R. et al. Hoxb8-Cre mice: A tool for brain-sparing conditional gene deletion. Genesis 48, 596–602 (2010).

    Article  CAS  Google Scholar 

  24. Vrieseling, E. & Arber, S. Target-induced transcriptional control of dendritic patterning and connectivity in motor neurons by the ETS gene Pea3. Cell 127, 1439–1452 (2006).

    Article  CAS  Google Scholar 

  25. Arber, S., Ladle, D.R., Lin, J.H., Frank, E. & Jessell, T.M. ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons. Cell 101, 485–498 (2000).

    Article  CAS  Google Scholar 

  26. Wilkinson, K.A., Kloefkorn, H.E. & Hochman, S. Characterization of muscle spindle afferents in the adult mouse using an in vitro muscle-nerve preparation. PLoS ONE 7, e39140 (2012).

    Article  CAS  Google Scholar 

  27. Brooks, S.V. & Faulkner, J.A. Contractile properties of skeletal muscles from young, adult and aged mice. J. Physiol. (Lond.) 404, 71–82 (1988).

    Article  CAS  Google Scholar 

  28. Adrian, E.D. & Zotterman, Y. The impulses produced by sensory nerve-endings. Part II. The response of a Single End-Organ. J. Physiol. (Lond.) 61, 151–171 (1926).

    Article  CAS  Google Scholar 

  29. de Nooij, J.C. et al. The PDZ-domain protein Whirlin facilitates mechanosensory signaling in mammalian proprioceptors. J. Neurosci. 35, 3073–3084 (2015).

    Article  CAS  Google Scholar 

  30. Lu, W., Bushong, E.A., Shih, T.P., Ellisman, M.H. & Nicoll, R.A. The cell-autonomous role of excitatory synaptic transmission in the regulation of neuronal structure and function. Neuron 78, 433–439 (2013).

    Article  CAS  Google Scholar 

  31. Zimmerman, A., Bai, L. & Ginty, D.D. The gentle touch receptors of mammalian skin. Science 346, 950–954 (2014).

    Article  CAS  Google Scholar 

  32. Coste, B. et al. Gain-of-function mutations in the mechanically activated ion channel PIEZO2 cause a subtype of Distal Arthrogryposis. Proc. Natl. Acad. Sci. USA 110, 4667–4672 (2013).

    Article  CAS  Google Scholar 

  33. Demireva, E.Y., Shapiro, L.S., Jessell, T.M. & Zampieri, N. Motor neuron position and topographic order imposed by beta- and gamma-catenin activities. Cell 147, 641–652 (2011).

    Article  CAS  Google Scholar 

  34. Kramer, I. et al. A role for Runx transcription factor signaling in dorsal root ganglion sensory neuron diversification. Neuron 49, 379–393 (2006).

    Article  CAS  Google Scholar 

  35. Hunt, C.C. & Kuffler, S.W. Stretch receptor discharges during muscle contraction. J. Physiol. (Lond.) 113, 298–315 (1951).

    Article  CAS  Google Scholar 

Download references


We thank B. Coste (Aix Marseille Université) for suggestions and H.U. Zeilhofer (University of Zurich) and R. Seal (University of Pittsburgh) for providing HoxB8-Cre mice. This work was supported by the Howard Hughes Medical Institute and US National Institutes of Health grant R01DE022358.

Author information

Authors and Affiliations



V.L. performed whole-cell electrophysiology in isolated DRG neurons. J.C.d.N. characterized Piezo2 cKO muscles in the laboratory of T.M.J. D.Z., C.R.C. and K.A.W. contributed to data collection and analyses for ex vivo muscle-nerve recordings in the laboratory of K.A.W. A.F. isolated DRG neurons for whole-cell electrophysiology. S.-H.W. contributed to all of the other experiments. S.-H.W., V.L., K.A.W. and A.P. wrote the manuscript.

Corresponding author

Correspondence to Ardem Patapoutian.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Integrated supplementary information

Supplementary Figure 1 Characterization of mechanically activated currents and Piezo2 expression in proprioceptive neurons.

a, Pvalb immunostaining with tdTomato epifluorescence in lumbar DRG from adult Pvalb-Cre;Ai9 mice. Scale bar: 100 μm. b, Current (I)-voltage (V) relationship of one mechanically activated IA current found in tdTomato+ neurons from adult Pvalb-Cre;Ai9 DRG. Voltage clamp experiments conducted identically to those depicted in Fig. 1b and c. Mechanically activated current responses to threshold plus 4-5 µm were used for I-V measurements.

Supplementary Figure 2 Characterization of GFP expression in Piezo2GFP lumbar DRG and skeletal muscles from hind leg.

a, Immunofluorescence for GFP and Pvalb in adult Piezo2GFP lumbar DRG. Circles mark cell bodies that co-express GFP and Pvalb. b, Immunofluorescence for GFP and Vglut1 in MSs and GTOs in various skeletal muscles from P8 Piezo2GFP hind leg. c, Immunofluorescence for GFP and αBTX (a marker of neuromuscular junction) in P6 Piezo2GFP hind leg muscle. Scale bars: a, 100 μm; b, 50 μm; c, 20 μm.

Supplementary Figure 3 Characterization of HoxB8-Cre;Ai9 DRG, skeletal muscles, and dorsal skin.

a, Based on caudal bias in the HoxB8-Cre activity, we assessed tdTomato epifluorescence in cervical/upper thoracic (left), lower thoracic (middle), and lumbar (right) DRG. tdTomato expression was sparse in neuronal cell bodies of cervical/upper thoracic (Th1-3) DRG stained with Piezo2 antibody (left). Strong tdTomato expression was detected in a majority of neuronal cell bodies in lower thoracic (middle) and lumbar (right) DRG stained with Piezo2 and Pvalb antibodies. White arrowheads mark tdTomato-cell bodies that express Piezo2 and Pvalb. This indicates that 1.5% (12/806) of total DRG neurons do not express HoxB8-Cre. b, tdTomato epifluorescence with Vglut1 immunostaining in proprioceptor endings in forelimb (left) and hind limb (right) muscles of adult HoxB8-Cre;Ai9 reporter. tdTomato was detected in MS endings and skeletal muscles of hind limbs, while it was absent in forelimb muscles and associated MSs. c, tdTomato epifluorescence with Nefh and DAPI staining in lanceolate endings (left, hair follicle) and with Nefh staining in Merkel cell-neurite complexes (right, touch dome) in adult HoxB8-Cre;Ai9 dorsal skin. Dotted line on left indicates the hair follicle, and the bracket marks lanceolate endings. Dotted circles on right mark Merkel cells, and the dotted line marks the epidermal-dermal junction. HS, hair shaft; TD, touch dome; GH, guard hair. Scale bars: a, 100 μm; b, 50 μm; c, 20 μm.

Supplementary Figure 4 Characterization of Pvalb-Cre;Piezo2cKO mice.

a, b, Piezo2 (green puncta) and Pvalb (red puncta) dual in situ hybridization in lumbar DRG of adult Piezo2fl/+ (WT, a) and Pvalb-Cre;Piezo2cKO mice (b). Left panels show entire DRG. Middle panels are the magnified view of dotted insets in the left panels. Smaller panels on right show the magnified view of the area marked with orange lines. White arrowheads in WT DRG (a) indicate Pvalb+ cell bodies with intact Piezo2. White circles in cKO DRG (b) indicate Pvalb+ cell bodies without Piezo2. White asterisk indicates one Pvalb+ cell body with intact Piezo2. 11.2% of Pvalb+ DRG neurons (10/89) still retained Piezo2 in Pvalb-Cre;Piezo2cKO mice. c, Quantification of MSs found in EDL (extensor digitorum longus) and soleus muscles from P10-11 WT and Pvalb-Cre;Piezo2cKO mice. Bars represent mean ± s.e.m. ns, not statistically significant. Unpaired t-test with Welch’s correction. d, Example images of Vglut1-stained MSs found in P30 WT and Pvalb-Cre;Piezo2cKO mice. e, Central projection of tdTomato+ proprioceptors in lumbar spinal cord of P5 Pvalb-Cre;Ai9 (WT) and Pvalb-Cre;Ai9;Piezo2cKO mice. Scale bars: a, b, e, 100 μm; d, 20 μm.

Supplementary Figure 5 Characterization of HoxB8-Cre;Piezo2cKO mice.

a, Piezo2 remaining (%) in cervical/upper thoracic (left) and lumbar (right) DRG from adult Piezo2fl/+ (WT) and HoxB8-Cre;Piezo2cKO mice by qRT-PCR. Note that HoxB8-Cre;Piezo2cKO mice refer to HoxB8-Cre;Piezo2fl/– (only one allele of Piezo2 is present prior to Cre recombination). Bars represent mean ± s.e.m. **P < 0.01; ****P < 0.0001. Unpaired t-test with Welch’s correction. b, Piezo2 (green puncta) in situ hybridization in lumbar DRG of adult Piezo2fl/+ (WT, top) and HoxB8-Cre;Piezo2cKO mice (bottom). Left panels show entire DRG outlined by solid lines. Right panels show the magnified view of dotted insets in the left panels. White asterisk (bottom, right) indicates one cell body with intact Piezo2. 1.2% of lumbar DRG neurons (2/165) still retained Piezo2 in HoxB8-Cre;Piezo2cKO mice, and this likely suggests that 1.2% of lumbar DRG neurons do not express HoxB8-Cre. c, Central projection of proprioceptors via Pvalb staining in lumbar spinal cord of P5 Piezo2fl/+ (WT) and HoxB8-Cre;Piezo2cKO mice. Scale bars: b, c, 100 μm.

Supplementary Figure 6 Maximal current responses observed in tdTomato+ neurons from adult Pvalb-Cre;Ai9 (WT) and Pvalb-Cre;Ai9;Piezo2cKO DRG.

Whole-cell voltage-clamp experiments from a holding potential of –60 mV. Mechanical stimulation was applied as described in Figures. 1 and 3. a, Individual data plot of maximal current densities of RA current responses. b, Individual data plot of maximal current densities of IA current responses.

Supplementary Figure 7 Activation of putative group III/IV acid-sensitive sensory neurons by pH 6.0 lactic acid in adult WT and Piezo2 cKO muscles.

Note that both Pvalb-Cre;Piezo2cKO and HoxB8-Cre;Piezo2cKO lines responded similarly. a, A typical WT response to pH 6.0 lactic acid with baseline firing activity. b, Lactic acid response in Piezo2 cKO mouse with no baseline firing activity.

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Woo, SH., Lukacs, V., de Nooij, J. et al. Piezo2 is the principal mechanotransduction channel for proprioception. Nat Neurosci 18, 1756–1762 (2015).

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:

This article is cited by


Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing