Biology subjects

Schwaller, F.

Publications and source records attributed to Schwaller, F..

4 recordsLinked to original sources

bioRxiv2022

Piezo2 voltage-block regulates mechanical pain sensitivity

PIEZO2 mechanosensitive channels are required for normal touch sensation. However, PIEZO2 channels are almost completely blocked at negative resting membrane potentials. We show that PIEZO2 voltage-block can be relieved by mutations at a conserved Arginine (R2756) which dramatically sensitizes the channel to mechanical stimuli. We generated Piezo2R2756H/R2756H and Piezo2R2756K/R2756K knock-in mice to ask how voltage regulates the endogenous mechanosensitivity of sensory neurons. Surprisingly, mechanosensitive currents in nociceptors, neurons that detect noxious mechanical stimuli, were substantially sensitized in Piezo2 knock-in mice, but touch receptors were largely unaffected. Piezo2 knock-in mice were hypersensitive to noxious mechanical stimuli as their nociceptors acquired properties similar to ultrasensitive touch receptors. Thus, mechanical pain sensitivity can be tuned by voltage-block of PIEZO2 channels, a channel property potentially amenable for pharmacological modulation.

neuroscience↗

bioRxiv2022

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

Touch sensation is primarily encoded by mechanoreceptors, called Low-Threshold Mechanoreceptors (LTMRs), with their cell bodies in the Dorsal Root Ganglia (DRG). Because of their great diversity in terms of molecular signature, terminal endings morphology and electrophysiological properties, mirroring the complexity of tactile experience, LTMRs are a model of choice to study the molecular cues differentially controlling neuronal diversification. While the transcriptional codes that define different LTMR subtypes have been extensively studied, the molecular players that participate in their late maturation and in particular in the striking diversity of their end-organ morphological specialization are largely unknown. Here we identified the TALE homeodomain transcription factor Meis2 as a key regulator of LTMRs target-field innervation. Meis2 is specifically expressed in cutaneous LTMRs and its expression depends on target-derived signals. While LTMRs lacking Meis2 survived and are normally specified, their end-organ innervations, electrophysiological properties and transcriptome are differentially and markedly affected, resulting in impaired sensory-evoked behavioral responses. These data establish Meis2 as a major transcriptional regulator controlling the orderly formation of sensory neurons innervating peripheral end-organs required for light touch.

developmental biology↗

bioRxiv2020

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

Fingertip mechanoreceptors comprise sensory neuron endings together with specialized skin cells that form the end-organ. Exquisitely sensitive vibration-sensing neurons are associated with Meissners corpuscles and Pacinian corpuscles1. 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 USH2A gene encodes a transmembrane protein with a very large extracellular domain. Pathogenic USH2A mutations cause Usher syndrome associated with hearing loss and visual impairment2. We show that patients with biallelic pathogenic USH2A 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 Ush2a-/- mice innervating Meissners 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 Meissners 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.

neuroscience↗

bioRxiv2018

The sensory coding of warm perception

Humans easily discriminate tiny skin temperature changes that are perceived as warming or cooling. Dedicated thermoreceptors forming distinct thermosensory channels or \"labelled lines\" are thought to underlie thermal perception. We show that mice have similar perceptual thresholds for forepaw warming to humans (~1 {degrees}C change) and do not mistake warming for cooling. Mice perform warm discrimination tasks without dedicated thermoreceptors, but use information carried by unmyelinated polymodal C-fibers. Deletion of the heat-sensitive transduction channels TRPM2 and TRPV1 did not impact warming perception or afferent coding of warm. However, without the cold sensitive TRPM8 channel, afferent coding of cooling was impaired and these mice cannot perceive warming or cooling. Our data is incompatible with the existence of thermospecific labelled lines, but can be reconciled by the existence of central circuits that compare and integrate the input from at least two types of polymodal afferents, hitherto thought to exclusively signal pain.

neuroscience↗