Scientific Understanding of Consciousness
Touch Receptors Tuned by Epidermal Merkel Cells
Nature 509, 617–621 (29 May 2014)
Epidermal Merkel cells are mechanosensory cells that tune mammalian touch receptors
Srdjan Maksimovic, et.al.
Department of Dermatology, Columbia University, New York, New York 10032, USA
Graduate School of System Design and Management, Keio University, Yokohama 223-8526, Japan
Department of Neuroscience, Baylor College of Medicine, Houston, Texas 77006, USA
Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla California 92037, USA
Department of Physiology & Cellular Biophysics, Columbia University, New York, New York 10032, USA
Program in Neurobiology & Behavior, Columbia University, New York, New York 10032, USA
Touch submodalities, such as flutter and pressure, are mediated by somatosensory afferents whose terminal specializations extract tactile features and encode them as action potential trains with unique activity patterns. Whether non-neuronal cells tune touch receptors through active or passive mechanisms is debated. Terminal specializations are thought to function as passive mechanical filters analogous to the cochlea’s basilar membrane, which deconstructs complex sounds into tones that are transduced by mechanosensory hair cells. The model that cutaneous specializations are merely passive has been recently challenged because epidermal cells express sensory ion channels and neurotransmitters; however, direct evidence that epidermal cells excite tactile afferents is lacking. Epidermal Merkel cells display features of sensory receptor cells and make ‘synapse-like’ contacts with slowly adapting type I (SAI) afferents. These complexes, which encode spatial features such as edges and texture, localize to skin regions with high tactile acuity, including whisker follicles, fingertips and touch domes. Here we show that Merkel cells actively participate in touch reception in mice. Merkel cells display fast, touch-evoked mechanotransduction currents. Optogenetic approaches in intact skin show that Merkel cells are both necessary and sufficient for sustained action-potential firing in tactile afferents. Recordings from touch-dome afferents lacking Merkel cells demonstrate that Merkel cells confer high-frequency responses to dynamic stimuli and enable sustained firing. These data are the first, to our knowledge, to directly demonstrate a functional, excitatory connection between epidermal cells and sensory neurons. Together, these findings indicate that Merkel cells actively tune mechanosensory responses to facilitate high spatio-temporal acuity. Moreover, our results indicate a division of labour in the Merkel cell–neurite complex: Merkel cells signal static stimuli, such as pressure, whereas sensory afferents transduce dynamic stimuli, such as moving gratings. Thus, the Merkel cell–neurite complex is an unique sensory structure composed of two different receptor cell types specialized for distinct elements of discriminative touch.
Our study sheds new light on the role of Merkel cells in touch reception. Our findings demonstrate that Merkel cells are touch-sensitive cells that actively tune mechanosensory afferents by conferring two features of the SAI response: sustained responses and high-frequency firing. First, by maintaining firing throughout mechanical stimulation, slowly adapting afferents inform the brain about pressure. Our optogenetic approach demonstrates that Merkel-cell activation elicits, and silencing reversibly suppresses, sustained SAI firing. This provides the first direct evidence that Merkel cells are not simply passive mechanical filters in the skin. Moreover, recordings from Atoh1CKO and Piezo2CKO mice show that SAI afferents cannot properly convey static phase information without intact Merkel cells. Second, during active tactile exploration, high-frequency firing is important for encoding object features (such as edges and curvature) with high information content. Although touch-dome afferents in Piezo2CKO showed similar dynamic responses to control mice, Atoh1CKO afferents showed markedly reduced dynamic firing. Thus, Merkel cells perform Piezo2-independent functions that enhance dynamic firing, which is predicted to facilitate high spatio-temporal acuity of tactile perception. Consistent with this prediction, Atoh1CKO mice display behavioural deficits in texture preference. These effects of Merkel-cell loss could be because of differences in SAI afferent development or touch-dome mechanics, or Piezo2-independent signalling mechanisms.
Our findings support two models for how Merkel cells contribute to the SAI afferent’s unique firing patterns. First, our data directly demonstrate that the Merkel cell–neurite complex is a compound sensory system with two receptor cell types that mediate different aspects of touch transduction. A similar division is found in the visual system, which also provides information on object shape and movement. In the retina, rods are optimized for low-light conditions and cones for high-acuity, colour vision. Second, the contribution of Merkel cells to dynamic firing indicates a previously unsuspected role in signal amplification, analogous to outer hair cells in the mammalian cochlea. These mechanosensory cells actively expend energy to tune the cochlea’s frequency selectivity and mechanical sensitivity. A key question that remains is the nature of the excitatory mechanisms that convey signals between Merkel cells and SAI afferents.
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Nature 509, 622–626 (29 May 2014)
Piezo2 is required for Merkel-cell mechanotransduction
Seung-Hyun Woo, et.al.
Howard Hughes Medical Institute, Molecular and Cellular Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA
Departments of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA
Departments of Dermatology & Physiology and Cellular Biophysics, Columbia University, New York, New York 10032, USA
Genomics Institute of the Novartis Research Foundation, San Diego, California 92121, USA
How we sense touch remains fundamentally unknown. The Merkel cell–neurite complex is a gentle touch receptor in the skin that mediates slowly adapting responses of Aβ sensory fibres to encode fine details of objects. This mechanoreceptor complex was recognized to have an essential role in sensing gentle touch nearly 50 years ago. However, whether Merkel cells or afferent fibres themselves sense mechanical force is still debated, and the molecular mechanism of mechanotransduction is unknown. Synapse-like junctions are observed between Merkel cells and associated afferents, and yet it is unclear whether Merkel cells are inherently mechanosensitive or whether they can rapidly transmit such information to the neighbouring nerve. Here we show that Merkel cells produce touch-sensitive currents in vitro. Piezo2, a mechanically activated 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, slowly adapting responses in vivo mediated by the Merkel cell–neurite complex show reduced static firing rates, and moreover, the mice display moderately decreased behavioural responses to gentle touch. Our results indicate that Piezo2 is the Merkel-cell mechanotransduction channel and provide the first line of evidence that Piezo channels have a physiological role in mechanosensation in mammals. Furthermore, our data present evidence for a two-receptor-site model, in which both Merkel cells and innervating afferents act together 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.
We recently discovered Piezo proteins as an evolutionarily conserved mechanically activated (MA) cation channel family. Drosophila melanogaster Piezo and zebrafish Piezo2b have been shown to be involved in somatosensory mechanotransduction. Of the two mammalian Piezo members, Piezo1 and Piezo2, Piezo2 is expressed in dorsal root ganglion (DRG) sensory neurons and is required for a subset of mechanically activated currents in DRGs. Here we focused on whether Piezo2 also has a role in somatosensory mechanotransduction in mammalian skin.
Activation of Merkel cells by gentle touch produces a long-lasting depolarization that may ultimately contribute to the slowly adapting firing of SAI nerve fibres that innervate them. Collectively, these data show for the first time that Merkel cells are indeed mechanosensitive, and that Piezo2 is required in Merkel cells to produce their mechanical currents in vitro.
Because Merkel cell–neurite complexes are known to mediate gentle touch sensation, we subjected these animals to tests for gentle touch, texture and pain, which included von Frey filaments, cotton swab sensitivity.
We have provided answers to critical questions regarding the functionality of the Merkel cell–neurite complex. Our study is the first, to our knowledge, to show that Merkel cells display touch-sensitive currents, and that Piezo2 is required for Merkel-cell mechanotransduction. This represents the first definitive evidence for a mammalian Piezo family member to be involved in mechanotransduction in vivo. Moreover, we show that Merkel cells have a partial role in the generation of slowly adapting responses and in gentle touch perception in mice. Interestingly, the accompanying manuscript demonstrates that Krt14Cre;Atoh1CKO animals, which completely lack epidermal Merkel cells in their skin, show similar SAI firing deficits as Piezo2 conditional knockout mice in skin–nerve recordings. This reinforces the hypothesis that Piezo2 is the principal Merkel-cell mechanotransduction channel in vivo. Our current data are most consistent with a two-receptor-site model, which proposes that both Merkel cells and Aβ sensory afferents are necessary for mediating proper mechanically activated slowly adapting responses. This model explains why slowly adapting fibres are only partially affected when Merkel cells are present but not mechanosensitive. The observed expression of Piezo2 in the afferents that innervate Merkel cells may also support this model. Analysis of the sensory afferent-specific Piezo2-deficient animal model will provide further clues to reveal the extent to which mechanotransduction is directly dependent on the nerves. Most peripheral sensory receptors are thought to have evolved with a single receptor site for sensory transduction. The Merkel cell–neurite complex is known to have the highest spatial resolution among other cutaneous mechanoreceptors, and this allows for deciphering fine spatial details such as shape, edge and curvature. We speculate that mechanosensors present both at nerve endings and in Merkel cells act together to convey the exquisite mechanosensitivity of this complex.
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