Peripheral somatosensation: a touch of genetics
Introduction
Five sensory systems (hearing, olfaction, somatosensation, taste, and vision) provide organisms with environmental information critical to their survival. Each system detects specific types of stimuli and transmits this information to the brain, where it is processed and integrated into sensory percepts, or constructs of the world around us. Of the five, only the somatosensory system is multimodal, detecting different types of stimuli including joint position (proprioception), noxious stimuli, temperature, and touch. Touch itself can be further subdivided into detection of curvature, hardness, shape, texture, pruriception (itch detection), and pleasurable touch [1, 2, 3]. The ability to detect and discriminate between these widely varied stimuli is achieved in mammalian skin by multiple sensory receptors specialized to provide modality-specific communication to the central nervous system [4].
Cell bodies of sensory neurons that innervate the periphery are located predominantly in cranial and dorsal root ganglia (DRGs) next to the spinal cord. These neurons possess a single axon that bifurcates to send one process into the dorsal spinal cord and the other to the skin [5]. Mature mammalian DRGs contain a heterogeneous population of neurons specialized for the detection of different somatosensory signals (Table 1) [1, 2, 6, 7, 8, 9, 10]. These cells can be classified on the basis of morphology, neurochemistry, and trophic requirements [5]. Here, we focus on recent developments that extend our knowledge of somatosensory mechanoreceptors.
Section snippets
Genetic specification and differentiation of somatosensory neurons
DRG neurons originate from neural crest cells (NCCs) that migrate ventrally from the dorsal neural tube during three distinct waves of migration (reviewed in [11]). Most adult DRG neurons derive from the second migratory wave, while NCCs in the first and third waves exhibit limited cell division [12, 13]. Each wave of NCC migration and neurogenesis gives rise to unique populations of DRG neuron subtypes [13, 14•]. NCCs of the first wave give rise to large mechanoreceptive and proprioceptive
The roles of neurotrophins
The neurotrophins (NTs) are a group of related molecules whose canonical role is to promote neuronal survival. NTs are expressed in sensory neuron target areas and mediate their effects through specific high-affinity receptors (NTRs) located on innervating axons. Each NT supports survival of different, sometimes overlapping, neuronal populations through restricted expression of NTRs. In adult mammalian DRGs, proprioceptors and slowly adapting type I low-threshold mechanoreceptors (LTMRs)
Sensory neuron projections
Proper targeting of sensory afferents requires coordinated neurite outgrowth, branching, and axon maintenance (reviewed in [76, 77]). Several signaling pathways modulate these processes (Figure 2).
NTs stimulate neurite outgrowth through actions separable from those that promote neuronal survival. Deletion of Bax in NGF-null, TrkA-null, NT3-null, and Ret-null mice rescues DRG neurons from apoptosis but alters central and peripheral projections [37, 78, 79]. These actions are modulated by Linx, a
The genetics of mechanotransduction
Mouse LTMRs become mechanotransduction-competent coincident with peripheral target innervation at the astonishingly early age of E13 [94•]. This ability is independent of NT3 activity but is consistent with changes in Runx3 expression that likely occur before target innervation [51, 95], suggesting that local determinants regulate Runx3 expression and define many aspects of mechanoreceptive (and proprioceptive) phenotypes.
Elucidation of the processes by which mechanical stimuli are transformed
Somatosensory cells in the skin
Merkel cells, a unique cell population found at the epidermal/dermal border, form complexes with slowly adapting type I nerve fibers. Merkel cells are derived from the epidermal lineage [101, 102] and express the transcription factor Atoh1, which is required for their production [103••]. Similar to their innervating neurons, Merkel cells exhibit NT dependence and are lost in BDNF-null, NGF-null, NT3-null, p75, TrkA-null, TrkB-null, and TrkC-null mice [29, 35, 36, 55]. Conversely,
Concluding remarks
Genetic animal models have provided invaluable insights into the mechanisms underlying peripheral somatosensory system development. However, several key questions remain. What genetic pathways control terminal differentiation of LTMR subclasses? How are cutaneous mechanoreceptors targeted to specific skin regions? And, at the most basic level, how do peripheral mechanoreceptors work? Newly developed genetic tools, such as combinatorial fate mapping and channelrhodopsins, should provide
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
We thank members of the Maricich Lab and Dr. Sharyl Fyffe-Maricich for critical review of this manuscript. We apologize to those whose work was not discussed due to space constraints. SMM is supported by NIH grants K08NS53419 (NINDS), P30AR39750 (NIAMS) and R01AR059114 (NIAMS).
References (106)
- et al.
Nociceptors—noxious stimulus detectors
Neuron
(2007) - et al.
The cutaneous sensory system
Neurosci Biobehav Rev
(2010) - et al.
Cutaneous innervation: form and function
J Am Acad Dermatol
(2005) - et al.
Thermoreceptors and thermosensitive afferents
Neurosci Biobehav Rev
(2010) - et al.
Unmyelinated afferents in human skin and their responsiveness to low temperature
Neurosci Lett
(2010) Itch and pain
Neurosci Biobehav Rev
(2010)- et al.
The neurophysiology of unmyelinated tactile afferents
Neurosci Biobehav Rev
(2010) - et al.
The boundary cap: a source of neural crest stem cells that generate multiple sensory neuron subtypes
Development
(2005) - et al.
SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells
Neuron
(2003) - et al.
Early specification of sensory neuron fate revealed by expression and function of neurogenins in the chick embryo
Development
(1999)
Transient expression of the bHLH factor neurogenin-2 marks a subpopulation of neural crest cells biased for a sensory but not a neuronal fate
Proc Natl Acad Sci USA
Characterization of sensory deficits in TrkB knockout mice
Neurosci Lett
Non-TrkA-expressing small DRG neurons are lost in TrkA deficient mice
J Neurosci
A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w
J Neurosci
The differential axonal degradation of Ret accounts for cell-type-specific function of glial cell line-derived neurotrophic factor as a retrograde survival factor
J Neurosci
Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not
Nature
Mice lacking brain-derived neurotrophic factor develop with sensory deficits
Nature
Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents
Cell
Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in mice lacking the neurotrophin receptor p75
Eur J Neurosci
Overexpression of brain-derived neurotrophic factor enhances sensory innervation and selectively increases neuron number
J Neurosci
Sensory but not motor neuron deficits in mice lacking NT4 and BDNF
Nature
Inhibition of the NT-3 receptor TrkC, early in chick embryogenesis, results in severe reductions in multiple neuronal subpopulations in the dorsal root ganglia
J Neurosci
Runx3 is required for the specification of TrkC-expressing mechanoreceptive trigeminal ganglion neurons
Mol Cell Neurosci
Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons
J Neurosci
Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons
J Neurosci
Signaling from axon guidance receptors
Cold Spring Harb Perspect Biol
LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development
Neuron
Neuropilin is a semaphorin III receptor
Cell
Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A
Mech Dev
Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors
Cell
A forward genetic screen in mice identifies Sema3A(K108N), which binds to neuropilin-1 but cannot signal
J Neurosci
Neuronal Nogo-A regulates neurite fasciculation, branching and extension in the developing nervous system
Development
Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons
J Neurosci
The fusogen EFF-1 controls sculpting of mechanosensory dendrites
Science
Adenylate cyclase 1 modulates peripheral nerve branching patterns
Mol Cell Neurosci
Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels
Science
Tactile functions of mechanoreceptive afferents innervating the hand
J Clin Neurophysiol
Peripheral sensory axon growth: from receptor binding to cellular signaling
Can J Neurol Sci
Vestibular, proprioceptive, and haptic contributions to spatial orientation
Annu Rev Psychol
Neural crest specification: migrating into genomics
Nat Rev Neurosci
Lineage of neurons and glia in chick dorsal root ganglia: analysis in vivo with a recombinant retrovirus
Development
Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS
Nat Neurosci
Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia
Genes Dev
Dynamic expression of neurotrophin receptors during sensory neuron genesis and differentiation
Dev Biol
Emergence of the sensory nervous system as defined by Foxs1 expression
Differentiation
Neurogenins, a novel family of atonal-related bHLH transcription factors, are putative mammalian neuronal determination genes that reveal progenitor cell heterogeneity in the developing CNS and PNS
Mol Cell Neurosci
Specification and connectivity of neuronal subtypes in the sensory lineage
Nat Rev Neurosci
Brn3a regulates the transition from neurogenesis to terminal differentiation and represses non-neural gene expression in the trigeminal ganglion
Dev Dyn
Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons
Nature
Targeted deletion of the mouse POU domain gene Brn-3a causes selective loss of neurons in the brainstem and trigeminal ganglion, uncoordinated limb movement, and impaired suckling
Proc Natl Acad Sci USA
Cited by (22)
Molecular basis of somatosensation in insects
2022, Current Opinion in NeurobiologyCitation Excerpt :Among type II mechanoreceptors, tracheal dendrite (td) neurons arborize around the trachea and are thought to mediate respiratory homeostasis [15], and bipolar dendrite (bd) neurons in the larvae extend dendrites between different body segments and play an important role in larvae locomotion [14]. Dendritic arborization (da) neurons are divided into four morphological groups based on their branching patterns: class I–IV neurons and function in tactile sensation and proprioception [1]. The dendrites of class I neurons are relatively long and smooth, and they branch with anteroposterior orientations.
The mechanisms of cold encoding
2022, Current Opinion in NeurobiologyCitation Excerpt :Our skin, teeth, muscles, bones, and joints are innervated by nerve endings belonging to a diverse array of peripheral sensory neurons, primed to respond to various forms of external and internal stimuli [1–4].
Objective neuromodulation basis for intrafascicular artificial somatosensation through carbon nanotube yarn electrodes
2022, Journal of Neuroscience MethodsCitation Excerpt :Peripheral somatosensation is fundamental to detect specific types of information involving touch, temperature, noxious inputs and joint positions (Campero and Bostock, 2010; Keysers et al., 2010; Olausson et al., 2010; Reed-Geaghan and Maricich, 2011; Saal and Bensmaia, 2014; Schepers and Ringkamp, 2010; Schmelz, 2010; Woolf and Ma, 2007).
Non-invasive transcranial ultrasound stimulation for neuromodulation
2022, Clinical NeurophysiologyCitation Excerpt :The theory generally states that the non-random mechanical deformation of the cell membrane leads to changes in both channel kinetics and membrane capacitance resulting in altered excitability. Although mechanosensation is a broadly studied feature of peripheral sensory systems (Reed-Geaghan and Maricich, 2011), mechanosensation has not readily been accepted for general neural response to ultrasound. This is possibly due to lower expression of relevant mechanosensors, and a less obvious need for mechanosensation in the brain.
Brief hind paw stimulation is sufficient to induce delayed somatosensory discrimination learning in C57BL/6 mice
2016, Behavioural Brain ResearchCitation Excerpt :Furthermore, tactile stimulation is closely associated with nursing, affiliative, and social behavior in mammals [3,4]. Thus, a large number of studies have been conducted to elucidate the neural and molecular mechanisms underlying somatic sensation in wide range of mammals, including humans [e.g.,5–8]. Rodent studies have primarily focused on the whiskers due to the distinctive structure of their corresponding primary sensory (barrel) cortex, and to the functional properties (e.g., fine movement and high sensitivity) of the whiskers.
Cutaneous tactile sensitivity before and after tail loss and regeneration in the leopard gecko (Eublepharis macularius)
2021, Journal of Experimental Biology