Peripheral somatosensation: a touch of genetics

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The somatosensory system processes information that organisms ‘feel’: joint position, muscle stretch, pain, pressure, temperature, and touch. The system is composed of a diverse array of peripheral nerve endings specialized to detect these sensory modalities. Several recent discoveries have shed light on the genetic pathways that control specification and differentiation of these neurons, how they accurately innervate their central and peripheral targets, and the molecules that enable them to detect mechanical stimuli. Here, we review the cadre of genes that control these processes, focusing on mechanosensitive neurons and support cells of the skin that mediate different aspects of the sense of touch.

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)

  • M. Zirlinger et al.

    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

    (2002)
  • P. Perez-Pinera et al.

    Characterization of sensory deficits in TrkB knockout mice

    Neurosci Lett

    (2008)
  • I. Silos-Santiago et al.

    Non-TrkA-expressing small DRG neurons are lost in TrkA deficient mice

    J Neurosci

    (1995)
  • M.F. Pazyra-Murphy et al.

    A retrograde neuronal survival response: target-derived neurotrophins regulate MEF2D and bcl-w

    J Neurosci

    (2009)
  • C.C. Tsui et al.

    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

    (2010)
  • V. Nikoletopoulou et al.

    Neurotrophin receptors TrkA and TrkC cause neuronal death whereas TrkB does not

    Nature

    (2010)
  • P. Ernfors et al.

    Mice lacking brain-derived neurotrophic factor develop with sensory deficits

    Nature

    (1994)
  • P. Ernfors et al.

    Lack of neurotrophin-3 leads to deficiencies in the peripheral nervous system and loss of limb proprioceptive afferents

    Cell

    (1994)
  • I. Kinkelin et al.

    Postnatal loss of Merkel cells, but not of slowly adapting mechanoreceptors in mice lacking the neurotrophin receptor p75

    Eur J Neurosci

    (1999)
  • A.M. LeMaster et al.

    Overexpression of brain-derived neurotrophic factor enhances sensory innervation and selectively increases neuron number

    J Neurosci

    (1999)
  • X. Liu et al.

    Sensory but not motor neuron deficits in mice lacking NT4 and BDNF

    Nature

    (1995)
  • F. Lefcort et al.

    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

    (1996)
  • K. Senzaki et al.

    Runx3 is required for the specification of TrkC-expressing mechanoreceptive trigeminal ganglion neurons

    Mol Cell Neurosci

    (2010)
  • A.M. Shadiack et al.

    Nerve growth factor antiserum induces axotomy-like changes in neuropeptide expression in intact sympathetic and sensory neurons

    J Neurosci

    (2001)
  • V.M. Verge et al.

    Differential influence of nerve growth factor on neuropeptide expression in vivo: a novel role in peptide suppression in adult sensory neurons

    J Neurosci

    (1995)
  • G.J. Bashaw et al.

    Signaling from axon guidance receptors

    Cold Spring Harb Perspect Biol

    (2010)
  • K. Mandai et al.

    LIG family receptor tyrosine kinase-associated proteins modulate growth factor signals during neural development

    Neuron

    (2009)
  • A.L. Kolodkin et al.

    Neuropilin is a semaphorin III receptor

    Cell

    (1997)
  • B. Rohm et al.

    Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A

    Mech Dev

    (2000)
  • T. Takahashi et al.

    Plexin-neuropilin-1 complexes form functional semaphorin-3A receptors

    Cell

    (1999)
  • J. Merte et al.

    A forward genetic screen in mice identifies Sema3A(K108N), which binds to neuropilin-1 but cannot signal

    J Neurosci

    (2010)
  • M.M. Petrinovic et al.

    Neuronal Nogo-A regulates neurite fasciculation, branching and extension in the developing nervous system

    Development

    (2010)
  • Z. Zhao et al.

    Regulate axon branching by the cyclic GMP pathway via inhibition of glycogen synthase kinase 3 in dorsal root ganglion sensory neurons

    J Neurosci

    (2009)
  • M. Oren-Suissa et al.

    The fusogen EFF-1 controls sculpting of mechanosensory dendrites

    Science

    (2010)
  • C. Haupt et al.

    Adenylate cyclase 1 modulates peripheral nerve branching patterns

    Mol Cell Neurosci

    (2010)
  • B. Coste et al.

    Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels

    Science

    (2010)
  • K.O. Johnson et al.

    Tactile functions of mechanoreceptive afferents innervating the hand

    J Clin Neurophysiol

    (2000)
  • B.A. Tucker et al.

    Peripheral sensory axon growth: from receptor binding to cellular signaling

    Can J Neurol Sci

    (2008)
  • J.R. Lackner et al.

    Vestibular, proprioceptive, and haptic contributions to spatial orientation

    Annu Rev Psychol

    (2005)
  • L.S. Gammill et al.

    Neural crest specification: migrating into genomics

    Nat Rev Neurosci

    (2003)
  • E. Frank et al.

    Lineage of neurons and glia in chick dorsal root ganglia: analysis in vivo with a recombinant retrovirus

    Development

    (1991)
  • G.S. Maro et al.

    Neural crest boundary cap cells constitute a source of neuronal and glial cells of the PNS

    Nat Neurosci

    (2004)
  • Q. Ma et al.

    Neurogenin1 and neurogenin2 control two distinct waves of neurogenesis in developing dorsal root ganglia

    Genes Dev

    (1999)
  • J.T. Rifkin et al.

    Dynamic expression of neurotrophin receptors during sensory neuron genesis and differentiation

    Dev Biol

    (2000)
  • A. Montelius et al.

    Emergence of the sensory nervous system as defined by Foxs1 expression

    Differentiation

    (2007)
  • L. Sommer et al.

    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

    (1996)
  • F. Marmigere et al.

    Specification and connectivity of neuronal subtypes in the sensory lineage

    Nat Rev Neurosci

    (2007)
  • J. Lanier et al.

    Brn3a regulates the transition from neurogenesis to terminal differentiation and represses non-neural gene expression in the trigeminal ganglion

    Dev Dyn

    (2009)
  • R.J. McEvilly et al.

    Requirement for Brn-3.0 in differentiation and survival of sensory and motor neurons

    Nature

    (1996)
  • M. Xiang et al.

    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

    (1996)
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