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Diversification and Specialization of Touch Receptors in Skin Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Diversification and Specialization of Touch Receptors in Skin David M. Owens1,2 and Ellen A. Lumpkin1,3 1Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, New York 10032 2Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York 10032 3Department of Physiology and Cellular Biophysics, Columbia University College of Physicians and Surgeons, New York, New York 10032 Correspondence: [email protected] Our skin is the furthest outpost of the nervous system and a primary sensor for harmful and innocuous external stimuli. As a multifunctional sensory organ, the skin manifests a diverse and highly specialized array of mechanosensitive neurons with complex terminals, or end organs, which are able to discriminate different sensory stimuli and encode this information for appropriate central processing. Historically, the basis for this diversity of sensory special- izations has been poorly understood. In addition, the relationship between cutaneous me- chanosensory afferents and resident skin cells, including keratinocytes, Merkel cells, and Schwann cells, during the development and function of tactile receptors has been poorly defined. In this article, we will discuss conserved tactile end organs in the epidermis and hair follicles, with a focus on recent advances in our understanding that have emerged from studies of mouse hairy skin. kin is our body’s protective covering and skills, including typing, feeding, and dressing Sour largest sensory organ. Unique among ourselves. Touch is also important for social ex- our sensory systems, the skin’s nervous system change, including pair bonding and child rear- www.perspectivesinmedicine.org gives rise to distinct sensations, including gentle ing (Tessier et al. 1998; Feldman et al. 2010). touch, pain, itch, warmth, and cold. These dis- Infants deprived of touch stimuli display devel- tinct percepts are initiated by an impressive ar- opmental and cognitive deficits (reviewed in ray of somatosensory neurons, whose sensory Kaffman and Meaney 2007; Ardiel and Rankin axons, called afferents, densely innervate the 2010). For example, premature babies show de- skin (Fig. 1). We rely on sensory inputs from layed development and growth but this can be the skin to interact with objects in our environ- improved by 45 minutes of daily touch stimula- ment and to avoid harm. tion. Cognitive deficits in touch-deprived rodent Our sense of touch enables us to perform pups persist through adulthood, highlighting numerous behaviors that rely on fine motor the importance of touch during development. Editors: Anthony E. Oro and Fiona M. Watt Additional Perspectives on The Skin and Its Diseases available at www.perspectivesinmedicine.org Copyright # 2014 Cold Spring Harbor Laboratory Press; all rights reserved; doi: 10.1101/cshperspect.a013656 Cite this article as Cold Spring Harb Perspect Med 2014;4:a013656 1 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press D.M. Owens and E.A. Lumpkin Receptor anatomy Neural signal Percept Guard/ tylotrich Aβ Touch dome RA Zigzag Slip, vibration, hair movements Epidermis SAI Shapes, textures, steady pressure Merkel cells Aδ Aδ-LTMR Hair movement ? AM Fast prickling pain C fibers Dermis C-nociceptor Slow burning pain, C-LTMR itch, sting Brushing Figure 1. Touch receptors of hairy skin. A diverse group of mechanosensory afferents innervate the hairy skin of mammals. The schematic depicts anatomically distinct end organs (right), which give rise to neural signals with distinct patterns of activity (center). These different classes of sensory neurons initiate the perception of different cutaneous sensations (left). Ab afferents (blue shades), which have thick myelin sheaths, are gentle-touch receptors that display rapidly adapting (RA) or slowly adapting (SA) responses to touch. In hairy skin, RA afferents form lanecolate endings around hair follicles. Slowly adapting type I (SAI) afferents innervate Merkel cells (yellow) clustered in touch domes. Ad afferents (green shades), which have thin myelin sheaths, include Ad low-threshold mechanoreceptors (LTMRs) and A-mechanonociceptors (AM), whose morphological end or- gans have not been identified. C-afferents (magenta shades) include C-LTMRsthat innervate hair follicles as well as pruritoceptors and nociceptors that innervate the epidermis. (Modified from Bautista and Lumpkin 2011.) Acute itch and pain are warning signals. ron et al. 2006; Liu and Ji 2013). These are Pain alerts us to noxious mechanical, chemical, prevalent complaints in developed countries. and thermal stimuli that have the potential to Chronic pain is estimated to afflict more than damage skin tissue. Moreover, under conditions 30% of Americans (Johannes et al. 2010). More- of inflammation or injury, skin displays a hyper- over, unrelieved itch is one of the most common sensitivity to touch and temperature that en- reasons for dermatological consult (Summery www.perspectivesinmedicine.org courages us to protect injured areas. Although 2009). the evolutionary advantage of itch is not fully Among the skin’s protective functions, understood, this sensation might provide pro- our understanding of cutaneous sensations tection by alerting us to the presence of insects has lagged compared with barrier and immune that have the potential to transmit disease. Itch functions. Recent studies of mouse models have sensation involves complex signaling between advanced our knowledge of the interactions keratinocytes, immune cells, and sensory neu- between skin and the nervous system that drives rons that innervate the epidermis (Liu and Ji sensation. Here, we focus on two mammalian 2013; Wilson et al. 2013). skin regions that are specialized for conveying In chronic pain and itch, these unpleasant touch stimuli to the nervous system—the touch sensations persist beyond the threat of tissue in- dome and the hair follicle. For additional in- jury. These chronic states accompany numerous sights into mechanosensory transduction, no- pathophysiological conditions, leading to pain ciception, and itch, we refer the reader to excel- triggered by gentle touch (allodynia), enhanced lent recent reviews (Basbaum et al. 2009; Chalfie sensitivity to noxious mechanical or thermal 2009; Jeffry et al. 2011; Patel and Dong 2011; Liu stimuli (hyperalgesia), and unrelieved itch (Gil- and Ji 2013). 2 Cite this article as Cold Spring Harb Perspect Med 2014;4:a013656 Downloaded from http://perspectivesinmedicine.cshlp.org/ on October 4, 2021 - Published by Cold Spring Harbor Laboratory Press Sensory Functions of the Skin MAMMALIAN SKIN IS INNERVATED BY ple, a surprising variety of rapidly adapting DISTINCT TYPES OF SENSORY NEURONS afferents innervate hair follicles to respond to brushing, stroking, or air movements (Li et al. Cutaneous sensory afferents display a diversity 2011). SA afferents respond to steady pressure of developmental programs, molecular recep- by producingdischargesthroughout skin stimu- tors, anatomical specializations, and neural sig- lation. The best characterized of these is the SA nals, which allow them to trigger distinct sen- type I (SAI) afferent, which forms complexes sations (Fig. 1). At the molecular level, different with Merkel cells located in the stratum basale classes of cutaneous sensory neurons are spec- of the epidermis. Other types of SA afferents ified by combinatorial expression of tran- also innervate skin; however, their end organs scription factors and distinct neurotrophin have not been identified in mice. Although the dependencies (reviewed in Liu and Ma 2011; correspondence between an end organ and its Lallemend and Ernfors 2012). Moreover, they neural firing pattern has traditionally been cor- express different receptors that can respond se- relative, recent studies have begun to identify lectively to chemicals, temperatures, or physical molecular markers that can be used to reli- forces (Lumpkin and Caterina 2007; Rice and ably distinguish afferent subtypes in mouse Albrecht 2008). When these sensory receptors skin (Loewenstein and Rathkamp 1958; Wood- are activated, they lead to membrane potential bury and Koerber 2007; Bourane et al. 2009; Luo changes that trigger discrete neural signals in et al. 2009; Seal et al. 2009; Li et al. 2011; Abraira the form of action potential trains with unique and Ginty 2013). patterns of activity. These neural signals are then Cutaneous afferents can also be classified processed by spinal cord and brain circuitry to based on the speed with which they conduct produce distinct percepts. action potentials, which is set by their degree Sensory afferents can be distinguished ana- of myelination (Brown and Iggo 1967; Rice tomically based on their sensory terminals, or and Albrecht 2008; Gardner et al. 2013). Ab end organs, in the skin (Fig. 1). Unmyelinated afferents are rapidly conducting fibers that afferents have free nerve endings that terminate have large axonal diameters and thick myelin in protrusions between epidermal keratino- sheaths. C fibers, which have thin, unmyelinat- cytes. These include pruritoceptors, which trig- ed afferents, are the slowest class. Ad fibers, ger itch; nociceptors, which evoke painful sen- which have fine axonal diameters and thin my- sations; and thermoreceptors, which respond to elin sheaths, display
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