Article | Published:

Piezo2 senses airway stretch and mediates lung inflation-induced apnoea

Nature volume 541, pages 176181 (12 January 2017) | Download Citation

Abstract

Respiratory dysfunction is a notorious cause of perinatal mortality in infants and sleep apnoea in adults, but the mechanisms of respiratory control are not clearly understood. Mechanical signals transduced by airway-innervating sensory neurons control respiration; however, the physiological significance and molecular mechanisms of these signals remain obscured. Here we show that global and sensory neuron-specific ablation of the mechanically activated ion channel Piezo2 causes respiratory distress and death in newborn mice. Optogenetic activation of Piezo2+ vagal sensory neurons causes apnoea in adult mice. Moreover, induced ablation of Piezo2 in sensory neurons of adult mice causes decreased neuronal responses to lung inflation, an impaired Hering–Breuer mechanoreflex, and increased tidal volume under normal conditions. These phenotypes are reproduced in mice lacking Piezo2 in the nodose ganglion. Our data suggest that Piezo2 is an airway stretch sensor and that Piezo2-mediated mechanotransduction within various airway-innervating sensory neurons is critical for establishing efficient respiration at birth and maintaining normal breathing in adults.

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Acknowledgements

We thank D. Trajkovic for assistance with histology; M. Wood for assistance with electron microscopy; J. Yu for suggesting that we test the Hering–Breuer reflex; S. M. Cahalan, M. Petrus, J. Mathur, K. Marshall, S. Lee, T. Kawamura, J. Chen and P. Paolo Sanna for technical assistance; and M. Krasnow for discussions. This research was supported by NIH grants R01DE022358 to A.P. and R01HL132255, and a Giovanni Armenise-Harvard Foundation Grant to S.D.L. A.P. is an investigator of the Howard Hughes Medical Institute.

Author information

Author notes

    • Keiko Nonomura
    • , Seung-Hyun Woo
    •  & Rui B. Chang

    These authors contributed equally to this work.

    • Zhaozhu Qiu
    •  & Sanjeev S. Ranade

    Present address: Department of Physiology and Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA (Z.Q.); The Gladstone Institute, San Francisco, California 94158, USA (S.S.R.).

Affiliations

  1. Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA

    • Keiko Nonomura
    • , Seung-Hyun Woo
    • , Zhaozhu Qiu
    • , Allain G. Francisco
    • , Sanjeev S. Ranade
    •  & Ardem Patapoutian
  2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Rui B. Chang
    •  & Stephen D. Liberles
  3. Howard Hughes Medical Institute, Department of Biochemistry, Stanford University School of Medicine, Stanford, California 94305, USA

    • Astrid Gillich
  4. Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA

    • Zhaozhu Qiu

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Contributions

A.G. characterized embryonic lungs in the laboratory of M. Krasnow. Z.Q. performed the initial characterization of Piezo2−/− mice. A.G.F. performed plethysmograph recordings and behavioural experiments to confirm Piezo2 knockdown. S.S.R. generated Piezo2fl/fl and Piezo2+/− mice. R.B.C. performed optogenetic experiments, whole vagus nerve electrophysiology recordings, and transducer-based Hering–Breuer reflex assessment in the S.D.L. laboratory. K.N. and S.-H.W. contributed equally to all other experiments. K.N., S.-H.W. and A.P. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding authors

Correspondence to Stephen D. Liberles or Ardem Patapoutian.

Reviewer Information Nature thanks M. Boehnke, J. M. Greally, B. Voight and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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https://doi.org/10.1038/nature20793

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