Merkel cells and neurons keep in touch

doi:10.1016/j.tcb.2014.10.003

Trends in Cell Biology

Volume 25, Issue 2, February 2015, Pages 74-81

https://doi.org/10.1016/j.tcb.2014.10.003 Get rights and content

Highlights

•
Merkel cells are touch-sensitive cells that transduce touch via Piezo2 channels.
•
The Merkel cell–neurite complex contains two sensory receptor cell types.
•
Merkel cells and neurons together mediate different aspects of touch responses.

The Merkel cell–neurite complex is a unique vertebrate touch receptor comprising two distinct cell types in the skin. Its presence in touch-sensitive skin areas was recognized more than a century ago, but the functions of each cell type in sensory transduction have been unclear. Three recent studies demonstrate that Merkel cells are mechanosensitive cells that function in touch transduction via Piezo2. One study concludes that Merkel cells, rather than sensory neurons, are principal sites of mechanotransduction, whereas two other studies report that both Merkel cells and neurons encode mechanical inputs. Together, these studies settle a long-standing debate on whether or not Merkel cells are mechanosensory cells, and enable future investigations of how these skin cells communicate with neurons.

Section snippets

Merkel cell–neurite complexes in skin

We depend on our sense of touch to gather information about the world around us and to accomplish skilled movements. Our ability to experience the richness of our tactile environment relies on touch receptors present in the skin. Touch receptors express mechanically activated (MA) ion channels that detect and convert mechanical stimuli into electrical signals. These electrical signals are then delivered to the central nervous system (CNS), where they are processed and interpreted as touch

A historical view of Merkel cells

The possibility that Merkel cells are sensory cells has been a subject of debate for decades. Some studies concluded that Merkel cells are mechanosensors, whereas others concluded that SAI afferents are primary sensory receptors, and that Merkel cells are accessory cells that modulate SAI responses 29, 33, 34, 35, 36, 37, 38. For example, phototoxic ablation of Merkel cells caused decreased SAI responses in one study [38], but showed no effect in another report [37]. A third group raised

Merkel cells are touch-sensitive cells with Piezo2-dependent transduction channels

Recently, important advances have been made to elucidate the function of Merkel cells in touch. Three independent studies report disparate set of experiments and provide direct evidence that Merkel cell are indeed touch-sensitive cells, and that they function as essential components of touch receptors in skin.

Two studies used a combination of mouse genetics and in vitro and intact electrophysiological recordings to examine the role of Merkel cells during touch transduction 48, 49, whereas a

How do Merkel cells communicate with SAI sensory neurons?

To understand mechanosensory signaling in Merkel cell–neurite complexes, the next important question to address is: how do Merkel cells excite SAI afferents? Ultrastructural studies and molecular profiling suggest that Merkel cells are presynaptic cells that communicate with afferent nerve terminals through synaptic transmission 10, 20, 30, 56, 57. Microarray analysis of purified Merkel cells from mouse skin has identified presynaptic active zone molecules, synaptic vesicle proteins, and

What is the role of Merkel cells in touch-evoked behaviors?

Different classes of LTMRs are tuned to selectively respond to specific mechanical stimuli (e.g., vibration, hair deflection, static pressure) 4, 40. What is special about the information that SAI afferents send to our brain that it warrants a dedicated cell type in the epidermis? First, SAI afferents densely innervate the skin (approximately 100 per cm² in our fingertips) [68]. Second, they have high sensitivity to points, edges and curvature [21]. Third, they have high spatial resolution as

Do Merkel cells shape responses of other cutaneous afferents?

Recent studies have suggested that touch domes are innervated by other fiber types in addition to Aβ afferents. Human touch domes are innervated by thickly myelinated, thinly myelinated and unmyelinated afferents that likely correspond to Aβ, Aδ, and C fibers, respectively [70]. In mouse skin, some touch domes have been reported to contain both thickly myelinated Aβ afferents and thinly myelinated, likely Aδ, afferents that contact Merkel cells [55]. Moreover, in neonatal touch domes, Merkel

Concluding remarks

Nearly 50-year-old mysteries of Merkel cell–neurite complexes are now at least partly solved: Merkel cells are touch-sensitive cells that transduce mechanical stimuli through Piezo2 MA cation channels, and they are required for proper output of SAI responses in tactile afferents. Moreover, the Merkel cell–neurite complex is a unique cutaneous sensory receptor containing two receptor cell types that mediate different aspects of touch-induced responses. The next important question to solve is the

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Cited by (116)

Merkel Cell Polyomavirus T Antigen–Mediated Reprogramming in Adult Merkel Cell Progenitors
2023, Journal of Investigative Dermatology
Whether Merkel cells regenerate in adult skin and from which progenitor cells they regenerate are a subject of debate. Understanding Merkel cell regeneration is of interest to the study of Merkel cell carcinoma, a rare neuroendocrine skin cancer hypothesized to originate in a Merkel cell progenitor transformed by Merkel cell polyomavirus small and large T antigens. We sought to understand what the adult Merkel cell progenitors are and whether they can give rise to Merkel cell carcinoma. We used lineage tracing to identify SOX9-expressing cells (SOX9+ cells) as Merkel cell progenitors in postnatal murine skin. Merkel cell regeneration from SOX9+ progenitors occurs rarely in mature skin unless in response to minor mechanical injury. Merkel cell polyomavirus small T antigen and functional imitation of large T antigen in SOX9+ cells enforced neuroendocrine and Merkel cell lineage reprogramming in a subset of cells. These results identify SOX9+ cells as postnatal Merkel cell progenitors that can be reprogrammed by Merkel cell polyomavirus T antigens to express neuroendocrine markers.
Three-dimensional reconstructions of mechanosensory end organs suggest a unifying mechanism underlying dynamic, light touch
2023, Neuron
Across mammalian skin, structurally complex and diverse mechanosensory end organs respond to mechanical stimuli and enable our perception of dynamic, light touch. How forces act on morphologically dissimilar mechanosensory end organs of the skin to gate the requisite mechanotransduction channel Piezo2 and excite mechanosensory neurons is not understood. Here, we report high-resolution reconstructions of the hair follicle lanceolate complex, Meissner corpuscle, and Pacinian corpuscle and the subcellular distribution of Piezo2 within them. Across all three end organs, Piezo2 is restricted to the sensory axon membrane, including axon protrusions that extend from the axon body. These protrusions, which are numerous and elaborate extensively within the end organs, tether the axon to resident non-neuronal cells via adherens junctions. These findings support a unified model for dynamic touch in which mechanical stimuli stretch hundreds to thousands of axon protrusions across an end organ, opening proximal, axonal Piezo2 channels and exciting the neuron.
Dynamic touch induces autonomic changes in preterm infants as measured by changes in heart rate variability
2023, Brain Research
Citation Excerpt :
On the other hand, clinical studies in adults have demonstrated that static touch can also activate the cerebral interoceptive network, likely due to the mediation of CT fibers as the researchers used low-threshold tactile stimuli (Cerritelli et al., 2017; Edwards et al., 2018). As a matter of fact, Merkel discs, which are known to respond to static touch, have been recognized as important neuroendocrine mediators for changes in local blood hemodynamics and musculature activity (Woo et al., 2015; Xiao et al., 2014). It is also noteworthy that some papers claimed that CT fibers can be found even in glabrous skin, and showed that stroking glabrous skin can be rated as pleasant as stroking hairy skin (Cruciani et al., 2021; Watkins et al., 2021).
Preterm birth significantly increases the risk of developing various long-term health problems and developmental disabilities. While touch is a crucial component of many perinatal care strategies, the neurobiological underpinnings are rarely considered. C-tactile fibers (CTs) are unmyelinated nerve fibers that are activated by low-force, dynamic touch. Touch directed specifically at CTs activates the posterior insular cortex, consistent with an interoceptive function, and has been shown to reduce heart rate and increase oxygen saturation. The current research compared the effect of five minutes of CT optimal velocity stroking touch versus five minutes of static touch on autonomic markers of preterm infants between 28 and 37 weeks gestational age. CT touch induces a higher increase in heart rate variability metrics related to the parasympathetic system, which persisted for a 5-minute post-touch period. Conversely, there was no such increase in infants receiving static touch. The present findings confirmed that CTs signal the affective quality of nurturing touch, thereby arguing an additional neurobiological substrate for the evident valuable impacts of neonatal tactile interventions and improving the effectiveness of such interventions.
Electromechanical model for object roughness perception during finger sliding
2022, Biophysical Journal
Touch allows us to gather abundant information in the world around us. However, how sensory cells embedded in the fingers convey texture information into their firing patterns is still poorly understood. Here, we develop an electromechanical model for roughness perception by incorporating main ingredients such as voltage-gated ion channels, active ion pumps, mechanosensitive channels, and cell deformation. The model reveals that sensory cells can convey texture wavelengths into the period of their firing patterns as the finger slides across object surfaces, but they can only convey a limited range of texture wavelengths. We also show that an increase in sliding speed broadens the decoding wavelength range at the cost of reduction of lower perception limits. Thus, a smaller sliding speed and a bigger contact force may be needed to successfully discern a smooth surface, consistent with previous psychophysical observations. Moreover, we show that cells with slowly adapting mechanosensitive channels can still fire action potentials under static loadings, indicating that slowly adapting mechanosensitive channels may contribute to the perception of coarse textures under static touch. Our work thus provides a new theoretical framework to study roughness perception and may have important implications for the design of electronic skin, artificial touch, and haptic interfaces.
Effects of potassium channel modulators on the responses of mammalian slowly adapting mechanoreceptors
2022, IBRO Neuroscience Reports
slowly adapting mechanoreceptors in the skin provide vital tactile information to animals. The ionic channels that underlie their functioning is the subject of intense research. Previous work suggests that potassium channels may play particular roles in the activation and firing of these mechanoreceptors.
We used a range of potassium channel blockers and openers to observe their effects on different phases of mechanoreceptor responses.
Extracellular recording of neural activity of slowly adapting mechanoreceptors was carried out in an in vitro preparation of the sinus hair follicles taken from rat whisker pads. A range of potassium (K⁺) channel modulators were tested on these mechanoreceptor responses. The channel blockers tested were: tetraethylammonium (TEA), barium chloride (BaCl₂), dequalinium, 4-aminopyridine (4-AP), paxilline, XE 991, apamin, and charybdotoxin.
Except for charybdotoxin and apamin, these drugs increased the activity of both types of slowly adapting units, St I and St II. Generally, both spontaneous and evoked (dynamic and static) activities increased. The channel opener NS1619 was also tested. NS1619 clearly decreased evoked activity (both dynamic and static) while leaving spontaneous activity relatively unaffected, with no clear discrimination of effects on the two types of St receptor
These findings are consistent with the targets of the drugs suggesting that K⁺ channels play an important role in the maintenance of spontaneous firing and in the production of and persistence of mechanoreceptor activity.
Reducing Merkel cell activity in the whisker follicle disrupts cortical encoding of whisker movement amplitude and velocity
2022, IBRO Neuroscience Reports
Citation Excerpt :
Their morphological, positional, and discharge features are factors determining their properties in encoding diverse features of whisker movement (Furuta et al., 2020; Gottschaldt et al., 1973). Among the most prominent whisker mechanoreceptors is the Merkel cell-neurite complex (Gottschaldt and Vahle-Hinz, 1981; Halata et al., 2003; Iggo and Muir, 1969; Woo et al., 2015) in which mechanically excitable cells (i.e. Merkel cells, MCs) synaptically excite primary trigeminal afferent neurons to fire SA impulses (Chang et al., 2016; Higashikawa et al., 2019; Hoffman et al., 2018; Ikeda et al., 2014; 1994; Maksimovic et al., 2014; Maricich et al., 2009; Nakatani et al., 2015; Woo et al., 2014; 2015). The activity of MCs strongly correlates with whisker displacement amplitude (Ikeda et al., 2014), and MC-associated afferents show robust coding of whisker self-movement, angle, and whisk-phase during whisking (Furuta et al., 2020; Severson et al., 2017).
Merkel cells (MCs) and associated primary sensory afferents of the whisker follicle-sinus complex, accurately code whisker self-movement, angle, and whisk phase during whisking. However, little is known about their roles played in cortical encoding of whisker movement. To this end, the spiking activity of primary somatosensory barrel cortex (wS1) neurons was measured in response to varying the whisker deflection amplitude and velocity in transgenic mice with previously established reduced mechanoelectrical coupling at MC-associated afferents. Under reduced MC activity, wS1 neurons exhibited increased sensitivity to whisker deflection. This appeared to arise from a lack of variation in response magnitude to varying the whisker deflection amplitude and velocity. This latter effect was further indicated by weaker variation in the temporal profile of the evoked spiking activity when either whisker deflection amplitude or velocity was varied. Nevertheless, under reduced MC activity, wS1 neurons retained the ability to differentiate stimulus features based on the timing of their first post-stimulus spike. Collectively, results from this study suggest that MCs contribute to cortical encoding of both whisker amplitude and velocity, predominantly by tuning wS1 response magnitude, and by patterning the evoked spiking activity, rather than by tuning wS1 response latency.

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Trends in Cell Biology

ReviewMerkel cells and neurons keep in touch

Highlights

Section snippets

Merkel cell–neurite complexes in skin

A historical view of Merkel cells

Merkel cells are touch-sensitive cells with Piezo2-dependent transduction channels

How do Merkel cells communicate with SAI sensory neurons?

What is the role of Merkel cells in touch-evoked behaviors?

Do Merkel cells shape responses of other cutaneous afferents?

Concluding remarks

Neuron

J. Invest. Dermatol.

Neurosci. Lett.

Neurosci. Lett.

J. Invest. Dermatol.

Curr. Opin. Neurobiol.

Curr. Opin. Neurobiol.

Dev. Biol.

Neurosci. Lett.

J. Invest. Dermatol.

Neuroscience

Cell

Curr. Biol.

J. Invest. Dermatol.

J. Invest. Dermatol.

Prog. Brain Res.

Neuroscience

Cell Rep.

The bodily senses

A quantitative study of cutaneous receptors and afferent fibres in the cat and rabbit

J. Physiol.

Three-dimensional microanatomy of longitudinal lanceolate endings in rat vibrissae

J. Comp. Neurol.

Sensory innervation of the hairy skin (light- and electronmicroscopic study

J. Invest. Dermatol.

Properties of cutaneous mechanoreceptors in the human hand related to touch sensation

Hum. Neurobiol.

Stimulus–response functions of rapidly adapting mechanoreceptors in human glabrous skin area

J. Physiol.

The sense of flutter-vibration: comparison of the human capacity with response patterns of mechanoreceptive afferents from the monkey hand

J. Neurophysiol.

The structure and function of a slowly adapting touch corpuscle in hairy skin

J. Physiol.

Tastzellen und Tastkörperchen bei den Hausthieren und beim Menschen

Archiv für Mikroskopische Anatomie

The distribution of Merkel cells in human fetal and adult skin

Am. J. Dermatopathol.

Anatomical mapping of Merkel cells in normal human adult epidermis

Br. J. Dermatol.

Friedrich Sigmund Merkel and his ‘Merkel cell’, morphology, development, and physiology: review and new results

Anat. Rec. A: Discov. Mol. Cell. Evol. Biol.

Evidence for glutamate receptor mediated transmission at mechanoreceptors in the skin

Neuroreport

Neuron-specific enolase in the Merkel cells of mammalian skin. The use of specific antibody as a simple and reliable histologic marker

Am. J. Pathol.

Neurotransmitters and synaptic components in the Merkel cell–neurite complex, a gentle-touch receptor

Ann. N. Y. Acad. Sci.

Vertebrate olfactory reception

Annu. Rev. Neurosci.

The receptors and cells for mammalian taste

Nature

The mechanical properties of ciliary bundles of turtle cochlear hair cells

J. Physiol.

Review
Merkel cells and neurons keep in touch