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      Piezo2 is required for Merkel cell mechanotransduction

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          Summary

          How we sense touch remains fundamentally unknown 1, 2 . The Merkel cell-neurite complex is a gentle touch receptor in the skin that mediates slowly-adapting (SA) responses of Aβ sensory fibers to encode fine details of objects 3- 6 . This mechanoreceptor complex was recognized to play an essential role in sensing gentle touch nearly 50 years ago 3, 4 . However, whether Merkel cells or afferent fibers themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown 1, 2, 7- 12 . Interestingly, synapse-like junctions are observed between Merkel cells and associated afferents 6, 13- 15 , and yet it is unclear if Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighboring nerve 1, 2, 16, 17 . Here we show for the first time that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically-activated (MA) cation channel, is expressed in Merkel cells. We engineered mice deficient in Piezo2 in the skin, but not in sensory neurons, and show that Merkel cell mechanosensitivity completely depends on Piezo2. In these mice, Merkel cell-neurite complex-mediated SA responses in vivo show reduced static firing rates, and moreover, they display moderately decreased behavioral responses to gentle touch. Our results indicate that Piezo2 is the Merkel cell mechanotransduction channel and provide the first line of evidence that Piezos play a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor site model, where both Merkel cells and innervating afferents act in concert as mechanosensors. The two-receptor system could provide this mechanoreceptor complex with a tuning mechanism to achieve highly sophisticated responses to a given mechanical stimulus 15, 18, 19 .

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          Most cited references34

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          Piezos are pore-forming subunits of mechanically activated channels

          Mechanotransduction plays a crucial role in physiology. Biological processes including sensing touch and sound waves require yet unidentified cation channels that detect pressure. Mouse piezo1 (mpiezo1) and mpiezo2 induce mechanically activated cationic currents in cells; however, it is unknown if piezos are pore-forming ion channels or modulate ion channels. We show that Drosophila piezo (dpiezo) also induces mechanically activated currents in cells, but through channels with remarkably distinct pore properties including sensitivity to the pore blocker ruthenium red and single channel conductances. mpiezo1 assembles as a ~1.2 million-Dalton tetramer, with no evidence of other proteins in this complex. Finally, purified mpiezo1 reconstituted into asymmetric lipid bilayers and liposomes forms ruthenium red-sensitive ion channels. These data demonstrate that piezos are an evolutionarily conserved ion channel family involved in mechanotransduction.
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            The roles and functions of cutaneous mechanoreceptors.

            K. Johnson (2001)
            Combined psychophysical and neurophysiological research has resulted in a relatively complete picture of the neural mechanisms of tactile perception. The results support the idea that each of the four mechanoreceptive afferent systems innervating the hand serves a distinctly different perceptual function, and that tactile perception can be understood as the sum of these functions. Furthermore, the receptors in each of those systems seem to be specialized for their assigned perceptual function.
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              Sonic hedgehog regulates growth and morphogenesis of the tooth.

              During mammalian tooth development, the oral ectoderm and mesenchyme coordinate their growth and differentiation to give rise to organs with precise shapes, sizes and functions. The initial ingrowth of the dental epithelium and its associated dental mesenchyme gives rise to the tooth bud. Next, the epithelial component folds to give the tooth its shape. Coincident with this process, adjacent epithelial and mesenchymal cells differentiate into enamel-secreting ameloblasts and dentin-secreting odontoblasts, respectively. Growth, morphogenesis and differentiation of the epithelium and mesenchyme are coordinated by secreted signaling proteins. Sonic hedgehog (Shh) encodes a signaling peptide which is present in the oral epithelium prior to invagination and in the tooth epithelium throughout its development. We have addressed the role of Shh in the developing tooth in mouse by using a conditional allele to remove Shh activity shortly after ingrowth of the dental epithelium. Reduction and then loss of Shh function results in a cap stage tooth rudiment in which the morphology is severely disrupted. The overall size of the tooth is reduced and both the lingual epithelial invagination and the dental cord are absent. However, the enamel knot, a putative organizer of crown formation, is present and expresses Fgf4, Wnt10b, Bmp2 and Lef1, as in the wild type. At birth, the size and the shape of the teeth are severely affected and the polarity and organization of the ameloblast and odontoblast layers is disrupted. However, both dentin- and enamel-specific markers are expressed and a large amount of tooth-specific extracellular matrix is produced. This observation was confirmed by grafting studies in which tooth rudiments were cultured for several days under kidney capsules. Under these conditions, both enamel and dentin were deposited even though the enamel and dentin layers remained disorganized. These studies demonstrate that Shh regulates growth and determines the shape of the tooth. However, Shh signaling is not essential for differentiation of ameloblasts or odontoblasts.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                29 April 2014
                06 April 2014
                29 May 2014
                29 November 2014
                : 509
                : 7502
                : 622-626
                Affiliations
                [1 ]Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, CA 92037, USA
                [2 ]Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI 53226, USA
                [3 ]Department of Dermatology & Physiology and Cellular Biophysics, Columbia University, New York, NY 10032, USA
                [4 ]Genomic Institute of the Novartis Research Foundation, San Diego, CA 92121, USA
                Author notes
                [†]

                Current address: Gladstone Institute of Neurological Disease, San Francisco, CA 94158

                Correspondence and requests for materials should be addressed to ardem@ 123456scripps.edu .
                Article
                NIHMS576012
                10.1038/nature13251
                4039622
                24717433
                ed5d0975-03b7-4a2a-80ba-e2837c1f52ff
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