title: Piezo2 is the major transducer of mechanical forces for touch sensation in mice.
abstract: The sense of touch provides critical information about our physical environment by transforming mechanical energy into electrical signals. It is postulated that mechanically activated cation channels initiate touch sensation, but the identity of these molecules in mammals has been elusive. 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 complexes. 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 neuron; however, major aspects of touch sensation remain intact without Merkel cell activity. 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.
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Sanjeev S
authors.initials: SS
authors.lastname: Ranade
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Woo
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Dubin
authors.affiliation: 1] Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straße 10, D-13092 Berlin, Germany [2] Klinik für Anästhesiologie mit Schwerpunkt Operative Intensivmedizin, Campus Charité Mitte and Virchow-Klinikum Charité, Universitätsmedizin Berlin, Augustburgerplatz 1, 13353 Berlin, Germany.
authors.forename: Rabih A
authors.initials: RA
authors.lastname: Moshourab
authors.affiliation: Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straße 10, D-13092 Berlin, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Wetzel
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Matt
authors.initials: M
authors.lastname: Petrus
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Jayanti
authors.initials: J
authors.lastname: Mathur
authors.affiliation: Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straße 10, D-13092 Berlin, Germany.
authors.forename: Valérie
authors.initials: V
authors.lastname: Bégay
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Coste
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: James
authors.initials: J
authors.lastname: Mainquist
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Wilson
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Allain G
authors.initials: AG
authors.lastname: Francisco
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Kritika
authors.initials: K
authors.lastname: Reddy
authors.affiliation: 1] Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA [2] Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA.
authors.forename: Zhaozhu
authors.initials: Z
authors.lastname: Qiu
authors.affiliation: Molecular Nociception Group, Wolfson Institute for Biomedical Research, University College London, London WC1E 6BT, UK.
authors.forename: John N
authors.initials: JN
authors.lastname: Wood
authors.affiliation: Department of Neuroscience, Max-Delbrück Center for Molecular Medicine, Robert-Rössle Straße 10, D-13092 Berlin, Germany.
authors.forename: Gary R
authors.initials: GR
authors.lastname: Lewin
authors.affiliation: Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, California 92037, USA.
authors.forename: Ardem
authors.initials: A
authors.lastname: Patapoutian
mesh_terms: D000818:Animals; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008465:Mechanoreceptors / Q000378:metabolism; D040542:Mechanotransduction, Cellular / Q000235:genetics / Q000502:physiology*; D018862:Merkel Cells / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D011984:Sensory Receptor Cells / Q000502:physiology; D012867:Skin / Q000294:innervation*; D014110:Touch / Q000235:genetics / Q000502:physiology*
chemical_list: D007473:Ion Channels; C552921:Piezo2 protein, mouse