Biology subjects

Lewin, G. R.

Publications and source records attributed to Lewin, G. R..

23 records · Page 2Linked to original sources

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↗

bioRxiv2018

The Pseudomonas aeruginosa Wsp pathway undergoes positive evolutionary selection during chronic infection

Author Contributions Author Contributions Introductory paragraph Results Discussion Materials and Methods References ESG and CWM performed the experimental work. JSH performed the colony PCR. SBC infected and sampled the porcine burn wounds. DS generated the sequence library. MW and GRL quantified the strain frequency in the wounds. ESG, CWM, MW, VSC, and DJW conceptualized the project and wrote the manuscript.\n\nIntroductory paragraph Author Contributions Introductory paragraph Results Discussion Materials and Methods References Pathogens experience pressure in an infection to adapt, with selection favoring mutants that persist. Pseudomonas aeruginosa commonly ad ...

microbiology↗

bioRxiv2018

Specialized mechanoreceptor systems in rodent glabrous skin

Rodents use their forepaws to actively interact with their tactile environment. Studies on the physiology and anatomy of glabrous skin that makes up the majority of the forepaw are almost non-existent in the mouse. Here we developed a preparation to record from single sensory fibers of the forepaw and compared anatomical and physiological receptor properties to those of the hind paw glabrous and hairy skin. We found that the mouse forepaw skin is equipped with a very high density of mechanoreceptors; >3 fold more than hind paw glabrous skin. In addition, rapidly adapting mechanoreceptors that innervate Meissners corpuscles of the forepaw were several-fold more sensitive to slowly moving mechanical stimuli compared to their counterparts in the hind paw glabrous skin. All other mechanoreceptors types as well as myelinated nociceptors had physiological properties that were invariant regardless of which skin area they occupied. We discovered a novel D-hair receptor innervating a small group of hairs in the middle of the hind paw glabrous skin in mice. Glabrous D-hair receptors were direction sensitive albeit with an orientation sensitivity opposite to that described for hairy skin D-hair receptors. Glabrous D-hair receptors do not occur in all rodents, but are present in North American and African rodent species that diverged more than 65 million years ago. The function of these specialized hairs is unknown, but they are nevertheless evolutionarily very ancient. Our study reveals novel physiological specializations of mechanoreceptors in the glabrous skin that likely evolved to facilitate tactile exploration.

neuroscience↗

bioRxiv2017

Voltage-gating of mechanosensitive PIEZO channels

Mechanosensitive PIEZO ion channels are evolutionarily conserved proteins whose presence is critical for normal physiology in multicellular organisms. Here we show that, in addition to mechanical stimuli, PIEZO channels are also powerfully modulated by voltage and can even switch to a purely voltage gated mode. Mutations that cause human diseases such as Xerocytosis profoundly shift voltage sensitivity of PIEZO1 channels towards the resting membrane potential and strongly promote pure voltage gating. Our data may be explained by the presence of an inactivation gate in the pore, the opening of which is promoted by outward permeation. Invertebrate (fly) and vertebrate (fish) PIEZO proteins are also voltage sensitive but voltage gating is a much more prominent feature of these older channels. We propose that the voltage sensitivity of PIEZO channels is a deep property co-opted to add a regulatory mechanism for PIEZO activation in widely different cellular contexts.

neuroscience↗