USH2A is a skin end-organ protein necessary for vibration sensing in mice and humans

Abstract

<jats:p>Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive vibration-sensing neurons are associated with Meissner’s corpuscles and Pacinian corpuscles<jats:sup>1</jats:sup>. Such end-organ structures have been recognized for more than 160 years, but their exact functions have remained a matter of speculation. Here we examined the role of USH2A in touch sensation in humans and mice. The <jats:italic>USH2A</jats:italic> gene encodes a transmembrane protein with a very large extracellular domain. Pathogenic <jats:italic>USH2A</jats:italic> mutations cause Usher syndrome associated with hearing loss and visual impairment<jats:sup>2</jats:sup>. We show that patients with biallelic pathogenic <jats:italic>USH2A</jats:italic> mutations also have profound impairments in vibrotactile touch perception. Similarly, mice lacking the USH2A protein showed severe deficits in a forepaw vibrotactile discrimination task. Forepaw rapidly-adapting mechanoreceptors (RAMs) recorded from <jats:italic>Ush2a</jats:italic><jats:sup><jats:italic>−/−</jats:italic></jats:sup> mice innervating Meissner’s corpuscles showed profound reductions in their vibration sensitivity. However, the USH2A protein was not expressed in sensory neurons, but was found in specialized terminal Schwann cells in Meissner’s corpuscles. Loss of this large extracellular tether-like protein in corpuscular end-organs innervated by RAMs was sufficient to reduce the vibration sensitivity of mechanoreceptors. Thus, USH2A expressed in corpuscular end-organs associated with vibration sensing is required to properly perceive vibration. We propose that cells within the corpuscle present a tether-like protein that may link to mechanosensitive channels in sensory endings to facilitate small amplitude vibration detection essential for the perception of fine textured surfaces.</jats:p>

Touch receptor end-organ innervation and function requires sensory neuron expression of the transcription factor Meis2

“…We used the Isl1 +/Cre ::Meis2 LoxP/LoxP mice to assess the effects of late loss of Meis2 on LTMR structure and function, and to investigate if post mitotic Meis2 inactivation impacts terminal morphologies and physiological properties of LTMRs. We made recordings from single mechanoreceptors and probed their responses to defined mechanical stimuli in adult WT, Isl1 +/Cre and Isl1 +/Cre ::Meis2 LoxP/LoxP mice using ex vivo skin nerve preparations as previously described (12,13,47).…”

“…Cutaneous mechanoreceptors or Low Threshold Mechanoreceptors (LMTRs) exhibit a variety of specialized terminal endings in the hairy and glabrous skin with strikingly unique morphologies (1-4, 6,7,11,12). LTMRs projecting to the glabrous skin innervate Merkel cell complexes or Meissner corpuscles at the dermal-epidermal border.…”

“…These were originally characterized as so-called field receptors (14,15) and were recently shown to form circumferential endings around hair follicles (16). LTMRs tuned to high frequency vibration are called Aβ-RAII and innervate Pacinian corpuscles deep in the skin or on the bone (12). Ruffini endings that are thought to be innervated by stretch sensitive mechanoreceptors (Aβ-SAII) remain poorly characterized in mice (3).…”

Lamellar cells in Pacinian and Meissner corpuscles are touch sensors

“…In Pacinian corpuscles, the mechanoreceptor is surrounded by onion-like sheaths formed by lamellar cells, whereas it is sandwiched between two or more lamellar cells in Meissner corpuscles. The functional role of lamellar cells is obscure, but they are thought to provide structural support for the neuronal afferent, facilitate small-amplitude vibrations (12), and serve as a passive mechanical filter for static stimuli (13). There are reports that some lamellar cells are immunoreactive for synaptic proteins, suggesting an active, rather than passive, role in touch sensing (14)(15)(16).…”

Lamellar cells in Pacinian and Meissner corpuscles are touch sensors

“…In layered corpuscles, the mechanoreceptor is surrounded by onion-like sheaths formed by lamellar cells, whereas it is sandwiched between two or more lamellar cells in non-layered corpuscles. The functional role of lamellar cells is obscure, but they are thought to provide structural support for the neuronal afferent, facilitate small-amplitude vibrations 12 and serve as a passive mechanical filter for static stimuli 13 . Interestingly, there are reports that some lamellar cells are immunoreactive for synaptic proteins, suggesting an active, rather than passive role in touch sensing [14][15][16] .…”