scholarly journals The development of cooperative channels explains the maturation of hair cell’s mechanotransduction

2019 ◽  
Author(s):  
Francesco Gianoli ◽  
Thomas Risler ◽  
Andrei S. Kozlov
Keyword(s):  
Ion Channels ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Hair Bundle ◽  
Mechanical Stimuli ◽  
Biophysical Properties ◽  
Tip Link ◽  
Fast Adaptation ◽  
Kinetics Of

ABSTRACTHearing relies on the conversion of mechanical stimuli into electrical signals. In vertebrates, this process of mechano-electrical transduction (MET) is performed by specialized receptors of the inner ear, the hair cells. Each hair cell is crowned by a hair bundle, a cluster of microvilli that pivot in response to sound vibrations, causing the opening and closing of mechanosensitive ion channels. Mechanical forces are projected onto the channels by molecular springs called tip links. Each tip link is thought to connect to a small number of MET channels that gate cooperatively and operate as a single transduction unit. Pushing the hair bundle in the excitatory direction opens the channels, after which they rapidly reclose in a process called fast adaptation. It has been experimentally observed that the hair cell’s biophysical properties mature gradually during postnatal development: the maximal transduction current increases, sensitivity sharpens, transduction occurs at smaller hair-bundle displacements, and adaptation becomes faster. Similar observations have been reported during tip-link regeneration after acoustic damage. Moreover, when measured at intermediate developmental stages, the kinetics of fast adaptation varies in a given cell depending on the magnitude of the imposed displacement. The mechanisms underlying these seemingly disparate observations have so far remained elusive. Here, we show that these phenomena can all be explained by the progressive addition of MET channels of constant properties, which populate the hair bundle first as isolated entities, then progressively as clusters of more sensitive, cooperative MET channels. As the proposed mechanism relies on the difference in biophysical properties between isolated and clustered channels, this work highlights the importance of cooperative interactions between mechanosensitive ion channels for hearing.SIGNIFICANCEHair cells are the sensory receptors of the inner ear that convert mechanical stimuli into electrical signals transmitted to the brain. Sensitivity to mechanical stimuli and the kinetics of mechanotransduction currents change during hair-cell development. The same trend, albeit on a shorter timescale, is also observed during hair-cell recovery from acoustic trauma. Furthermore, the current kinetics in a given hair cell depends on the stimulus magnitude, and the degree of that dependence varies with development. These phenomena have so far remained unexplained. Here, we show that they can all be reproduced using a single unifying mechanism: the progressive formation of channel pairs, in which individual channels interact through the lipid bilayer and gate cooperatively.

scholarly journals FGFR1-mediated protocadherin-15 loading mediates cargo specificity during intraflagellar transport in inner ear hair-cell kinocilia

2018 ◽  
Vol 115 (33) ◽  
pp. 8388-8393 ◽  
Author(s):  
Akira Honda ◽  
Tomoko Kita ◽  
Shri Vidhya Seshadri ◽  
Kazuyo Misaki ◽  
Zamal Ahmed ◽  
...  
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Primary Cilia ◽  
Growth Factor Receptor ◽  
Intraflagellar Transport ◽  
Hair Bundle ◽  
Mechanical Stimuli ◽  
Transport Pathway ◽  
Protocadherin 15

The mechanosensory hair cells of the inner ear are required for hearing and balance and have a distinctive apical structure, the hair bundle, that converts mechanical stimuli into electrical signals. This structure comprises a single cilium, the kinocilium, lying adjacent to an ensemble of actin-based projections known as stereocilia. Hair bundle polarity depends on kinociliary protocadherin-15 (Pcdh15) localization. Protocadherin-15 is found only in hair-cell kinocilia, and is not localized to the primary cilia of adjacent supporting cells. Thus, Pcdh15 must be specifically targeted and trafficked into the hair-cell kinocilium. Here we show that kinocilial Pcdh15 trafficking relies on cell type-specific coupling to the generic intraflagellar transport (IFT) transport mechanism. We uncover a role for fibroblast growth factor receptor 1 (FGFR1) in loading Pcdh15 onto kinociliary transport particles in hair cells. We find that on activation, FGFR1 binds and phosphorylates Pcdh15. Moreover, we find a previously uncharacterized role for clathrin in coupling this kinocilia-specific cargo with the anterograde IFT-B complex through the adaptor, DAB2. Our results identify a modified ciliary transport pathway used for Pcdh15 transport into the cilium of the inner ear hair cell and coordinated by FGFR1 activity.

scholarly journals The Mechanosensory Transduction Machinery in Inner Ear Hair Cells

2020 ◽  
Vol 50 (1) ◽  
Author(s):  
Wang Zheng ◽  
Jeffrey R. Holt
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Annual Review ◽  
Publication Date ◽  
Fusion Partner ◽  
Mechanical Stimuli ◽  
Physical Stimulation ◽  
Mechanosensory Transduction ◽  
Protocadherin 15

Sound-induced mechanical stimuli are detected by elaborate mechanosensory transduction (MT) machinery in highly specialized hair cells of the inner ear. Genetic studies of inherited deafness in the past decades have uncovered several molecular constituents of the MT complex, and intense debate has surrounded the molecular identity of the pore-forming subunits. How the MT components function in concert in response to physical stimulation is not fully understood. In this review, we summarize and discuss multiple lines of evidence supporting the hypothesis that transmembrane channel-like 1 is a long-sought MT channel subunit. We also review specific roles of other components of the MT complex, including protocadherin 15, cadherin 23, lipoma HMGIC fusion partner-like 5, transmembrane inner ear, calcium and integrin-binding family member 2, and ankyrins. Based on these recent advances, we propose a unifying theory of hair cell MT that may reconcile most of the functional discoveries obtained to date. Finally, we discuss key questions that need to be addressed for a comprehensive understanding of hair cell MT at molecular and atomic levels. Expected final online publication date for the Annual Review of Biophysics, Volume 50 is May 6, 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

scholarly journals Par3 is essential for the establishment of planar cell polarity of inner ear hair cells

2019 ◽  
Vol 116 (11) ◽  
pp. 4999-5008 ◽  
Author(s):  
Andre Landin Malt ◽  
Zachary Dailey ◽  
Julia Holbrook-Rasmussen ◽  
Yuqiong Zheng ◽  
Arielle Hogan ◽  
...  
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Cell Polarity ◽  
Hair Cells ◽  
Planar Cell Polarity ◽  
Tissue Level ◽  
Hair Bundle ◽  
Nucleotide Exchange ◽  
Genetic Mosaic ◽  
Pcp Signaling

In the inner ear sensory epithelia, stereociliary hair bundles atop sensory hair cells are mechanosensory apparatus with planar polarized structure and orientation. This is established during development by the concerted action of tissue-level, intercellular planar cell polarity (PCP) signaling and a hair cell-intrinsic, microtubule-mediated machinery. However, how various polarity signals are integrated during hair bundle morphogenesis is poorly understood. Here, we show that the conserved cell polarity protein Par3 is essential for planar polarization of hair cells. Par3 deletion in the inner ear disrupted cochlear outgrowth, hair bundle orientation, kinocilium positioning, and basal body planar polarity, accompanied by defects in the organization and cortical attachment of hair cell microtubules. Genetic mosaic analysis revealed that Par3 functions both cell-autonomously and cell-nonautonomously to regulate kinocilium positioning and hair bundle orientation. At the tissue level, intercellular PCP signaling regulates the asymmetric localization of Par3, which in turn maintains the asymmetric localization of the core PCP protein Vangl2. Mechanistically, Par3 interacts with and regulates the localization of Tiam1 and Trio, which are guanine nucleotide exchange factors (GEFs) for Rac, thereby stimulating Rac-Pak signaling. Finally, constitutively active Rac1 rescued the PCP defects in Par3-deficient cochleae. Thus, a Par3–GEF–Rac axis mediates both tissue-level and hair cell-intrinsic PCP signaling.

scholarly journals Good vibrations: Music and the single hair cell

2002 ◽  
Vol 24 (6) ◽  
pp. 12-14
Author(s):  
Corné Kros
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Auditory Nerve ◽  
Sound Stimulus ◽  
Mechanical Stimuli ◽  
Sensory Receptors ◽  
Nerve Fibres ◽  
Sound Processing ◽  
The Brain

Hair cells are the sensory receptors in the inner ear, and the hair bundles that protrude from their upper surfaces transduce mechanical stimuli into electrical responses. This article examines the key molecules involved in the different stages of sound processing within these extraordinarily sensitive and intricate cells, from the reception of the sound stimulus to the release of neurotransmitters on to the auditory nerve fibres that signal to the brain that a sound has been received.

scholarly journals A Reversal in Hair Cell Orientation Organizes Both the Auditory and Vestibular Organs

2021 ◽  
Vol 15 ◽  
Author(s):  
Basile Tarchini
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Sensory Epithelium ◽  
Mirror Image ◽  
Hair Bundle ◽  
Directional Sensitivity ◽  
Mechanical Stimuli ◽  
Cell Orientation ◽  
Auditory Hair Cells ◽  
Organ Level

Sensory hair cells detect mechanical stimuli with their hair bundle, an asymmetrical brush of actin-based membrane protrusions, or stereocilia. At the single cell level, stereocilia are organized in rows of graded heights that confer the hair bundle with intrinsic directional sensitivity. At the organ level, each hair cell is precisely oriented so that its intrinsic directional sensitivity matches the direction of mechanical stimuli reaching the sensory epithelium. Coordinated orientation among neighboring hair cells usually ensures the delivery of a coherent local group response. Accordingly, hair cell orientation is locally uniform in the auditory and vestibular cristae epithelia in birds and mammals. However, an exception to this rule is found in the vestibular macular organs, and in fish lateral line neuromasts, where two hair cell populations show opposing orientations. This mirror-image hair cell organization confers bidirectional sensitivity at the organ level. Here I review our current understanding of the molecular machinery that produces mirror-image organization through a regional reversal of hair cell orientation. Interestingly, recent evidence suggests that auditory hair cells adopt their normal uniform orientation through a global reversal mechanism similar to the one at work regionally in macular and neuromast organs. Macular and auditory organs thus appear to be patterned more similarly than previously appreciated during inner ear development.

scholarly journals The 133-kDa N-terminal domain enables myosin 15 to maintain mechanotransducing stereocilia and is essential for hearing

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Qing Fang ◽  
Artur A Indzhykulian ◽  
Mirna Mustapha ◽  
Gavin P Riordan ◽  
David F Dolan ◽  
...  
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Knockout Mouse ◽  
Molecular Motor ◽  
Hair Bundle ◽  
Terminal Domain

The precise assembly of inner ear hair cell stereocilia into rows of increasing height is critical for mechanotransduction and the sense of hearing. Yet, how the lengths of actin-based stereocilia are regulated remains poorly understood. Mutations of the molecular motor myosin 15 stunt stereocilia growth and cause deafness. We found that hair cells express two isoforms of myosin 15 that differ by inclusion of an 133-kDa N-terminal domain, and that these isoforms can selectively traffic to different stereocilia rows. Using an isoform-specific knockout mouse, we show that hair cells expressing only the small isoform remarkably develop normal stereocilia bundles. However, a critical subset of stereocilia with active mechanotransducer channels subsequently retracts. The larger isoform with the 133-kDa N-terminal domain traffics to these specialized stereocilia and prevents disassembly of their actin core. Our results show that myosin 15 isoforms can navigate between functionally distinct classes of stereocilia, and are independently required to assemble and then maintain the intricate hair bundle architecture.

Hes1 is a negative regulator of inner ear hair cell differentiation

Development ◽  
2000 ◽  
Vol 127 (21) ◽  
pp. 4551-4560 ◽  
Author(s):  
J.L. Zheng ◽  
J. Shou ◽  
F. Guillemot ◽  
R. Kageyama ◽  
W.Q. Gao
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Hair Cells ◽  
Outer Hair Cells ◽  
Negative Regulator ◽  
Pcr Analysis ◽  
Loss Of Function ◽  
Hair Cell Differentiation

Hair cell fate determination in the inner ear has been shown to be controlled by specific genes. Recent loss-of-function and gain-of-function experiments have demonstrated that Math1, a mouse homolog of the Drosophila gene atonal, is essential for the production of hair cells. To identify genes that may interact with Math1 and inhibit hair cell differentiation, we have focused on Hes1, a mammalian hairy and enhancer of split homolog, which is a negative regulator of neurogenesis. We report here that targeted deletion of Hes1 leads to formation of supernumerary hair cells in the cochlea and utricle of the inner ear. RT-PCR analysis shows that Hes1 is expressed in inner ear during hair cell differentiation and its expression is maintained in adulthood. In situ hybridization with late embryonic inner ear tissue reveals that Hes1 is expressed in supporting cells, but not hair cells, of the vestibular sensory epithelium. In the cochlea, Hes1 is selectively expressed in the greater epithelial ridge and lesser epithelial ridge regions which are adjacent to inner and outer hair cells. Co-transfection experiments in postnatal rat explant cultures show that overexpression of Hes1 prevents hair cell differentiation induced by Math1. Therefore Hes1 can negatively regulate hair cell differentiation by antagonizing Math1. These results suggest that a balance between Math1 and negative regulators such as Hes1 is crucial for the production of an appropriate number of inner ear hair cells.

High-Voltage Electron Microscopic Study of the Inner Ear: Technique and Preliminary Results

1983 ◽  
Vol 92 (1_suppl) ◽  
pp. 3-12 ◽  
Author(s):  
Tomonori Takasaka ◽  
Hideich Shinkawa ◽  
Kozo Watanuki ◽  
Sho Hashimoto ◽  
Kazutomo Kawamoto
Keyword(s):  
Electron Microscopy ◽  
Hair Cell ◽  
Inner Ear ◽  
High Voltage ◽  
Hair Cells ◽  
Outer Hair Cells ◽  
Tectorial Membrane ◽  
Preliminary Results ◽  
Voltage Electron ◽  
Cuticular Plate

The technique and some preliminary results of the application of high-voltage electron microscopy (HVEM) to the study of inner ear morphology in the guinea pig are reported in this paper. The main advantage of HVEM is that sharp images of thicker specimens can be obtained because of the greater penetrating power of high energy electrons. The optimum thickness of the sections examined with an accelerating voltage of 1,000 kV was found to be between 500 to 800 nm. The sections below 500 nm in thickness often had insufficient contrast, while those above 800 nm were rather difficult to interpret due to overlap of images of the organelles. The whole structure of the sensory hairs from the tip to the rootlet was more frequently observed in the 800-nm thick sections. Thus the fine details of the hair attachment to the tectorial membrane as well as the hair rootlet extension into the cuticular plate could be thoroughly studied in the HVEM. In specimens fixed in aldehyde containing 2% tannic acid, the attachment of the tips of the outer hair cell stereocilia to the tectorial membrane was observed. For the inner hair cells, however, the tips of the hairs were separated from the undersurface of the tectorial membrane. The majority of the rootlets of the outer hair cells terminated at the midportion of the cuticular plate, while most of the inner hair cell rootlets traversed the entire width of the cuticular plate and extended into the apical cytoplasm. These differences in ultrastructural appearance may indicate that the two kinds of hair cells play different roles in the acoustic transduction process. The three-dimensional arrangement of the nerve endings on the hair cells was also studied by the serial thick-sectioning technique in the HVEM. In general, an entire arrangement of the nerve endings was almost completely cut in less than ten 800-nm thick sections instead of the 50- to 100-ultrathin (ie, less than 100 nm) conventional sections for transmission electron microscopy. The present study confirms an earlier report that the first row outer hair cells in the third cochlear turn are innervated by nearly equal numbers of efferent and afferent endings, the average number being nine.

scholarly journals In Silico Electrophysiology of Inner-Ear Mechanotransduction Channel TMC1 Models

2021 ◽  
Author(s):  
Sanket Walujkar ◽  
Jeffrey M Lotthammer ◽  
Collin R Nisler ◽  
Joseph C Sudar ◽  
Angela Ballesteros ◽  
...  
Keyword(s):  
Inner Ear ◽  
Conformational Changes ◽  
Hair Cells ◽  
Head Movements ◽  
Mechanical Stimuli ◽  
Ion Conduction ◽  
Sensory Hair Cells ◽  
Activation Mechanisms ◽  
Dynamics Simulations ◽  
Molecular Components

Inner-ear sensory hair cells convert mechanical stimuli from sound and head movements into electrical signals during mechanotransduction. Identification of all molecular components of the inner-ear mechanotransduction apparatus is ongoing; however, there is strong evidence that TMC1 and TMC2 are pore-forming subunits of the complex. We present molecular dynamics simulations that probe ion conduction of TMC1 models built based on two different structures of related TMEM16 proteins. Unlike most channels, the TMC1 models do not show a central pore. Instead, simulations of these models in a membrane environment at various voltages reveal a peripheral permeation pathway that is exposed to lipids and that shows cation permeation at rates comparable to those measured in hair cells. Furthermore, our analyses suggest that TMC1 gating mechanisms involve protein conformational changes and tension-induced lipid-mediated pore widening. These results provide insights into ion conduction and activation mechanisms of hair-cell mechanotransduction channels essential for hearing and balance.

Delta1 expression during avian hair cell regeneration

Development ◽  
1999 ◽  
Vol 126 (5) ◽  
pp. 961-973 ◽  
Author(s):  
J.S. Stone ◽  
E.W. Rubel
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Cell Injury ◽  
Basilar Papilla ◽  
Cell Regeneration ◽  
Mrna Levels ◽  
Hair Cell Regeneration ◽  
Drug Induced ◽  
In Cells

Postembryonic production of hair cells, the highly specialized receptors for hearing, balance and motion detection, occurs in a precisely controlled manner in select species, including avians. Notch1, Delta1 and Serrate1 mediate cell specification in several tissues and species. We examined expression of the chicken homologs of these genes in the normal and drug-damaged chick inner ear to determine if signaling through this pathway changes during hair cell regeneration. In untreated post-hatch chicks, Delta1 mRNA is abundant in a subpopulation of cells in the utricle, which undergoes continual postembryonic hair cell production, but it is absent from all cells in the basilar papilla, which is mitotically quiescent. By 3 days after drug-induced hair cell injury, Delta1 expression is highly upregulated in areas of cell proliferation in both the utricle and basilar papilla. Delta1 mRNA levels are elevated in progenitor cells during DNA synthesis and/or gap 2 phases of the cell cycle and expression is maintained in both daughter cells immediately after mitosis. Delta1 expression remains upregulated in cells that differentiate into hair cells and is downregulated in cells that do not acquire the hair cell fate. Delta1 mRNA levels return to normal by 10 days after hair cell injury. Serrate1 is expressed in both hair cells and support cells in the utricle and basilar papilla, and its expression does not change during the course of drug-induced hair cell regeneration. In contrast, Notch1 expression, which is limited to support cells in the quiescent epithelium, is increased in post-M-phase cell pairs during hair cell regeneration. This study provides initial evidence that Delta-Notch signaling may be involved in maintaining the correct cell types and patterns during postembryonic replacement of sensory epithelial cells in the chick inner ear.

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