USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans

Schwaller, Fred; Bégay, Valérie; García‐García, Gema; Taberner, Francisco J.; Moshourab, Rabih; McDonald, Brennan; Docter, Trevor; Kühnemund, Johannes; Ojeda-Alonso, Julia; Paricio-Montesinos, Ricardo; Lechner, Stefan; Poulet, James F.A.; Millán, José María; Lewin, Gary R.

doi:10.1038/s41593-020-00751-y

Cited by 58 publications

(73 citation statements)

References 45 publications

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“…In addition, we find that the brain is largely insulated, or 'cloaked', from shear waves by the cranium and that the shear waves are largely carried away from the skull by the vertebral column, which acts as a waveguide. Our calculations further suggest that off-target skin locations are excited to levels such as may induce sensory responses in the subject [30,31,32,33]. Our findings also reveal that shear stresses, but not pressures, exhibit a consistent and marked dependence on the FUS frequency, with lower frequencies leading to stronger shear effects, in agreement with observations of UNM effects in rodents [10,3].…”

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confidence: 87%

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Mechanics Of Ultrasonic Neuromodulation In A Mouse Subject

Salahshoor

Guo

Shapiro

et al. 2021

Preprint

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Ultrasound neuromodulation (UNM), where a region in the brain is targeted by focused ultrasound (FUS), which, in turn, causes excitation or inhibition of neural activity, has recently received considerable attention as a promising tool for neuroscience. Despite its great potential, several aspects of UNM are still unknown. An important question pertains to the off-target sensory effects of UNM and their dependence on stimulation frequency. To understand these effects, we have developed a finite-element model of a mouse, including elasticity and viscoelasticity, and used it to interrogate the response of mouse models to focused ultrasound (FUS). We find that, while some degree of focusing and magnification of the signal is achieved within the brain, the induced pressure-wave pattern is complex and delocalized. In addition, we find that the brain is largely insulated, or 'cloaked', from shear waves by the cranium and that the shear waves are largely carried away from the skull by the vertebral column, which acts as a waveguide. We find that, as expected, this waveguide mechanism is strongly frequency dependent, which may contribute to the frequency dependence of UNM effects. Our calculations further suggest that off-target skin locations experience displacements and stresses at levels that, while greatly attenuated from the source, could nevertheless induce sensory responses in the subject.

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confidence: 87%

“…The peak displacements computed at the neck and face are 0.8 µm and 0.91 µm, respectively. The computed off-target mechanical stresses and deformations, though small, may nevertheless be of sufficient magnitude to elicit a sensory response [30,31,32,33].…”

mentioning

confidence: 99%

Mechanics Of Ultrasonic Neuromodulation In A Mouse Subject

Salahshoor

Guo

Shapiro

et al. 2021

Preprint

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“…Numerous tissues have cilia; thus, any genetic variation that alters ciliary functions could affect different organs. Several additional signs have been described in USH patients related to cilia function: bronchiectasis [157], olfactory loss [158,159], subclinical nasal ciliary beat frequency [160], nociception [161], reduced sperm motility [162] and somatosensory deficit [163][164][165]. However, further evidence is still necessary to consider these characteristics as being USH-related comorbidities.…”

Section: Is Ush Actually a Ciliopathy?mentioning

confidence: 99%

Usher Syndrome: Genetics of a Human Ciliopathy

Fuster-García

García‐Bohórquez

Rodríguez-Muñoz

et al. 2021

IJMS

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Usher syndrome (USH) is an autosomal recessive syndromic ciliopathy characterized by sensorineural hearing loss, retinitis pigmentosa and, sometimes, vestibular dysfunction. There are three clinical types depending on the severity and age of onset of the symptoms; in addition, ten genes are reported to be causative of USH, and six more related to the disease. These genes encode proteins of a diverse nature, which interact and form a dynamic protein network called the “Usher interactome”. In the organ of Corti, the USH proteins are essential for the correct development and maintenance of the structure and cohesion of the stereocilia. In the retina, the USH protein network is principally located in the periciliary region of the photoreceptors, and plays an important role in the maintenance of the periciliary structure and the trafficking of molecules between the inner and the outer segments of photoreceptors. Even though some genes are clearly involved in the syndrome, others are controversial. Moreover, expression of some USH genes has been detected in other tissues, which could explain their involvement in additional mild comorbidities. In this paper, we review the genetics of Usher syndrome and the spectrum of mutations in USH genes. The aim is to identify possible mutation associations with the disease and provide an updated genotype–phenotype correlation.

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“…TMC1 is particularly interesting, because despite the fact that it can be activated by force-from-lipids in liposomes, it still requires an intracellular tether for activation in intact cells 38,54 , which indicates that one cannot draw definitive conclusions about relevant in-vivo gating mechanisms based on inherent stretch sensitivity. There is also evidence for the requirement of an extracellular tether for normal mechanosensitivity of primary sensory afferents in which PIEZO2 mediates mechanotransduction 55,56 . Moreover, a contribution of the cytoskeleton to PIEZO channel activation seems highly likely, considering the observation that disruption of the cytoskeleton with Cytochalasin-D renders PIEZO1…”

Section: Discussionmentioning

confidence: 99%

“An intrinsically disordered intracellular domain of PIEZO2 is required for force-from-filament activation of the channel”

Verkest

Schaefer

Jegelka

et al. 2021

Preprint

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A central question in mechanobiology is how mechanical forces acting in or on a cell are transmitted to mechanically-gated PIEZO channels that convert these forces into biochemical signals. Here we show that PIEZO2 is sensitive to force-transmission via the membrane (force-from-lipids) as well as force transmission via the cytoskeleton (force-from-filament) and demonstrate that the latter requires the intracellular linker between the transmembrane helices nine and ten (IDR5). Moreover, we show that rendering PIEZO2 insensitive to force-from-filament by deleting IDR5 abolishes PIEZO2-mediated inhibition of neurite outgrowth, which relies on the detection of cellgenerated traction forces, while it only partially affects its sensitivity to cell indentation and does not at all alter its sensitivity to membrane stretch. Hence, we propose that PIEZO2 is a polymodal mechanosensor that detects different types of mechanical stimuli via different force transmission pathways, which highlights the importance of utilizing multiple complementary assays when investigating PIEZO channel function.

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USH2A is a Meissner’s corpuscle protein necessary for normal vibration sensing in mice and humans

Cited by 58 publications

References 45 publications

Mechanics Of Ultrasonic Neuromodulation In A Mouse Subject

Mechanics Of Ultrasonic Neuromodulation In A Mouse Subject

Usher Syndrome: Genetics of a Human Ciliopathy

“An intrinsically disordered intracellular domain of PIEZO2 is required for force-from-filament activation of the channel”

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