The hair cells of the inner ear seem to be specified properly as they express many of the typical hair cell markers such as myosin VI/VIIa, Math1 and Brn3c. Thus, Gfi1 is not required for the specification of hair cells as they are formed in both the vestibule and the cochlea. However, the loss of Gfi1 seems to affect the vestibular and cochlear hair cells differently. In the vestibule, the hair cells are morphologically abnormal at the earliest stages of hair cell differentiation and at all subsequent stages. In addition, hair cells are not specifically localized to a lumenal monolayer, and are more variable in size and shape. This disorganization of hair cells in the vestibule may account for the ataxic behavior of the mice. In the cochlea, Gfi1 is required for the organization and maintenance of both inner and outer hair cells. Although the mutant hair cells seem to be specified in the developing organ of Corti as early as E15.5 and express typical hair cell markers, they are disorganized. In ...
TY - JOUR. T1 - Regeneration of Stereocilia of Hair Cells by Forced Atoh1 Expression in the Adult Mammalian Cochlea. AU - Yang, Shi Ming. AU - Chen, Wei. AU - Guo, Wei Wei. AU - Jia, Shuping. AU - Sun, Jian He. AU - Liu, Hui Zhan. AU - Young, Wie Yen. AU - He, David Z.Z.. PY - 2012/9/27. Y1 - 2012/9/27. N2 - The hallmark of mechanosensory hair cells is the stereocilia, where mechanical stimuli are converted into electrical signals. These delicate stereocilia are susceptible to acoustic trauma and ototoxic drugs. While hair cells in lower vertebrates and the mammalian vestibular system can spontaneously regenerate lost stereocilia, mammalian cochlear hair cells no longer retain this capability. We explored the possibility of regenerating stereocilia in the noise-deafened guinea pig cochlea by cochlear inoculation of a viral vector carrying Atoh1, a gene critical for hair cell differentiation. Exposure to simulated gunfire resulted in a 60-70 dB hearing loss and extensive damage and loss of ...
OBJECTIVE/HYPOTHESIS: Hair cells of the mammalian auditory system do not regenerate, and therefore their loss leads to irreversible hearing loss. Aminoglycosides, among other substances, can irreversibly damage hair cells. Somatostatin, a peptide with hormone/neurotransmitter properties, has neuroprotective effects by binding to its receptor. In this study, we tested whether somatostatin can protect hair cells from gentamicin-induced damage in vitro. STUDY DESIGN: This study confirmed the expression of somatostatin receptor mRNA within the cochlea and analyzed the effect of somatostatin on gentamicin-induced hair cell damage and death in vitro. METHODS: Expression of somatostatin receptor mRNA in the rat cochlea was analyzed by reverse transcriptase-polymerase chain reaction (RT-PCR). Protection of auditory hair cells from gentamicin was tested using two different concentrations (1 microM and 5 microM, respectively) of somatostatin. RESULTS: We detected somatostatin receptor-1 and -2 mRNA and in ...
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 ...
Death of sensory hair cells in the inner ear results in two global health problems that millions of people around the world suffer: hearing loss and balance disorders. Hair cells convert sound vibrations and head movements into electrical signals that are conveyed to the brain, and as a result of aging, exposure to noise, modern drugs or genetic predisposition, hair cells die. In mammals, the great majority of hair cells are produced during embryogenesis, and hair cells that are lost after birth are not replaceable. However, in the last decades, researches have shown some model organisms that retain the ability to regenerate hair cells damaged after embryogenesis, such as Zebrafish and chicken, providing clues as to the cellular and molecular mechanisms that may block hair cell regeneration in mammals. This discovery initiated a search for methods to stimulate regeneration or replacement of hair cells in mammals, a search that, if fruitful, will revolutionize the treatment of hearing loss and ...
In fish, amphibians, and birds, regeneration of sensory hair cells through asymmetric cell divisions of supporting cells can contribute to recovery of hearing and balance after hair cell loss caused by trauma or toxicity (1, 2). Mammalian hair cells do not spontaneously regenerate, even though supporting cells in vestibular sensory epithelia retain a limited ability to divide (3, 4). Consequently, hair cell death in mammals often leads to permanent impairment of hearing and balance.. As the inner ear develops, hair cell progenitor cells exit from the cell cycle and, like neurons, terminally differentiate. Negative cell cycle regulators apparently maintain the postmitotic status of hair cells and contribute to their terminal differentiation. The cyclin-dependent kinase inhibitors p27Kip1 and p19Ink4d participate in cell cycle exit of hair cell progenitors and in hair cell apoptosis, respectively (5, 6). However, the key regulators of cell cycle exit and concomitant hair cell terminal ...
Mature mammals exhibit very limited capacity for regeneration of auditory hair cells, while all non-mammalian vertebrates examined can regenerate them. In an effort to find therapeutic targets for deafness and balance disorders, scientists have examined gene expression patterns in auditory tissues under different developmental and experimental conditions. Microarray technology has allowed the large-scale study of gene expression profiles (transcriptomics) at whole-genome levels, but since mRNA expression does not necessarily correlate with protein expression, other methods, such as microRNA analysis and proteomics, are needed to better understand the process of hair cell regeneration. These technologies and some of the results of them are discussed in this review. Although there is a considerable amount of variability found between studies owing to different species, tissues and treatments, there is some concordance between cellular pathways important for hair cell regeneration. Since gene expression
Hair cells, the sensory receptors of the auditory, vestibular, and lateral-line organs, may be damaged by a number of agents including aminoglycoside antibiotics and severe overstimulation. In the avian cochlea, lost hair cells can be replaced by regeneration. These new hair cells appear to be derived from a support cell precursor which is stimulated to divide by events associated with hair cell loss. Little is known about the timing and sequencing of events leading to new hair cell production. In this study cell cycle-associated events in the avian cochlea were analyzed at early and late time intervals following a single high dose of gentamicin. This single dose protocol has been shown to consistently result in extensive morphological damage and hair cell loss in the proximal region of the cochlea while sparing a morphologically undamaged distal cochlear region. This allowed for the differential analysis of the underlying support cell populations with respect to local hair cell loss. Three cell ...
in Ear, Nose, & Throat Journal (1998), 77(4), 276280282-5. Regeneration/repair and protection of auditory hair cells and auditory neurons is an exciting, rapidly evolving field. Simultaneous developments in the fields of otobiology and surgical otology have led ... [more ▼]. Regeneration/repair and protection of auditory hair cells and auditory neurons is an exciting, rapidly evolving field. Simultaneous developments in the fields of otobiology and surgical otology have led to new and exciting possibilities in inner ear medicine and surgery; specifically, the treatment or prevention of a variety of types of hearing losses in the foreseeable future. Sensorineural hearing loss in humans is commonly associated with a loss of auditory hair cells. It has been generally accepted that hearing loss resulting from hair cell damage is irreversible because the human ear has been considered to be incapable of regenerating or repairing these sensory elements following severe injury. An organ of Corti ...
Wnt signaling is a highly conserved pathway crucial for development and homeostasis of multicellular organisms. Secreted Wnt ligands bind Frizzled receptors to regulate diverse processes such as axis patterning, cell division, and cell fate specification. They also serve to govern self-renewal of somatic stem cells in several adult tissues. The complexity of the pathway can be attributed to the myriad of Wnt and Frizzled combinations as well as its diverse context-dependent functions. In the developing mouse inner ear, Wnt signaling plays diverse roles, including specification of the otic placode and patterning of the otic vesicle. At later stages, its activity governs sensory hair cell specification, cell cycle regulation, and hair cell orientation. In regenerating sensory organs from non-mammalian species, Wnt signaling can also regulate the extent of proliferative hair cell regeneration. This review describes the current knowledge of the roles of Wnt signaling and Wnt-responsive cells in hair cell
Cochlear hair cells are mechanoreceptors of the auditory system and cannot spontaneously regenerate in adult mammals; thus hearing loss due to hair cell damage is permanent. In contrast, hair cells...
In my PhD (Bristol University, 1983) I used ion-sensitive microelectrodes to investigate pH regulation in snail neurones, supervised by Dr RC Thomas. I was awarded a Royal Society Exchange Fellowship to work in Paris (ENS), mainly with Dr Alain Marty on the muscarinic response in rat lacrimal glands, but also did some single channel work and a characterisation of a novel calcium-activated chloride current. I then switched direction towards hearing and the cochlea, doing a postdoc in Denver (UCHSC) with Dr Paul Fuchs following a short period in Bristol. We investigated the electrical resonance mechanism in chick cochlear hair cells. I next investigated the hair cell transduction mechanism in turtles, working with Andrew Crawford and Robert Fettiplace in Cambridge. In 1990 I became a temporary lecturer in Physiology, Bristol, and two years later was awarded a Wellcome Trust postdoctoral fellowship to investigate the mechanism of efferent inhibition in cochlear outer hair cells. This has been my ...
Inner-ear hair cell differentiation requires Atoh1 function, while Eya1, Six1, and Sox2 are coexpressed in sensory progenitors and mutations in these genes cause sensorineural hearing loss. However, how these genes are linked functionally and the transcriptional networks controlling hair cell induct …
Hair cell loss in the cochlea is caused by ototoxic drugs, aging, and environmental stresses and could potentially lead to devastating pathophysiological effects. In adult mammals, hair cell loss is irreversible and may result in hearing and balance deficits. In contrast, nonmammalian vertebrates, including birds, can regenerate hair cells through differentiation of supporting cells and restore inner ear function, suggesting that hair cell progenitors are present in the population of supporting cells. In the present study, we aimed to identify novel genes related to regeneration in the chicken utricle by gene expression profiling of supporting cell and hair cell populations obtained by laser capture microdissection. The volcano plot identified 408 differentially expressed genes (twofold change, p = 0.05, Benjamini-Hochberg multiple testing correction), 175 of which were well annotated. Among these genes, we focused on Musashi-1 (MSI1), a marker of neural stem cells involved in Notch signaling, and the
Clarin-1, a tetraspan-like membrane protein defective in Usher syndrome type IIIA (USH3A), is essential for hair bundle morphogenesis in auditory hair cells. We report a new synaptic role for clarin-1 in mouse auditory hair cells elucidated by characterization of Clrn1 total (Clrn1ex4-/-) and postnatal hair cell-specific conditional (Clrn1ex4fl/fl Myo15-Cre+/-) knockout mice. Clrn1ex4-/- mice were profoundly deaf, whereas Clrn1ex4fl/fl Myo15-Cre+/- mice displayed progressive increases in hearing thresholds, with, initially, normal otoacoustic emissions and hair bundle morphology. Inner hair cell (IHC) patch-clamp recordings for the 2 mutant mice revealed defective exocytosis and a disorganization of synaptic F-actin and CaV1.3 Ca2+ channels, indicative of a synaptopathy. Postsynaptic defects were also observed, with an abnormally broad distribution of AMPA receptors associated with a loss of afferent dendrites and defective electrically evoked auditory brainstem responses. Protein-protein ...
The avian basilar papilla is composed of hair and supporting cells arranged in a regular pattern in which the hair cells are surrounded and isolated from each other by supporting cell processes. This arrangement of cells, in which the apical borders of hair cells do not contact one another, may be generated by contact-mediated lateral inhibition. Little is known, however, about the way in which hair and supporting cells are organized during development. Whole mounts double-labeled with antibodies to the 275 kDa hair-cell antigen and the tight junction protein cingulin were therefore used to examine the development of cell patterns in the basilar papilla. Hair cells that contact each other at their apical borders are seen during early development, especially on embryonic days (E) 8 and 9, but are no longer observed after E12. Hair and supporting cell patterns were analyzed in three different areas of the papilla at E9 and E12. In two of these regions between E9 and E12, the ratio of supporting ...
Prevention of auditory hair cell death offers therapeutic potential to rescue hearing. Pharmacological blockade of JNK/c-Jun signaling attenuates injury-induced hair cell loss, but with unsolved mechanisms. We have characterized the c-Jun stress response in the mouse cochlea challenged with acoustic overstimulation and ototoxins, by studying the dynamics of c-Jun N-terminal phosphorylation. It occurred acutely in glial-like supporting cells, inner hair cells and in the cells of the cochlear ion trafficking route, and was rapidly downregulated after exposures. Notably, death-prone outer hair cells lacked c-Jun phosphorylation. As phosphorylation was triggered also by non-traumatic noise levels and as none of the cells showing this activation were lost, c-Jun phosphorylation is a biomarker for cochlear stress rather than an indicator of a death-prone fate of hair cells. Preconditioning with a mild noise exposure before a stronger traumatizing noise exposure attenuated the cochlear c-Jun stress ...
Introduction and Objective]: The cochleogram is a graphic record which represents hair cells along the length of the basilar membrane and relates cell damage with frequency specific values in hearing thresholds. The purpose of this study is to design a simple and robust method to quantitatively determine the distribution of the inner and outer hair cells at the organ of Corti in the mouse cochlea. [Materials and Methods]: Six male CBA/CaOlaHsd mice with normal auditory brainstem responses were sacrificed at 2months of age. The cochleae from both ears (n=12) were extracted, fixed and decalcified, and then divided in two parts (apical-middle and basal), obtaining around 80% of the whole extent of the basilar membrane. The organ of Corti (OC) was isolated and phalloidin-stained in multiwall glass slides. Using a fluorescence microscope and stereological software, the total length of the OC was divided into equidistant 5% sectors1. The number of inner (IHC) and outer (OHC) hair cells in randomly ...
Research on the regrowth of cochlear cells may lead to medical treatments that restore hearing. Unlike birds and fish, humans and other mammals are generally incapable of regrowing the cells of the inner ear that convert sound into neural signals when those cells are damaged by age or disease.[4][20] Researchers are making progress in gene therapy and stem-cell therapy that may allow the damaged cells to be regenerated. Because hair cells of auditory and vestibular systems in birds and fish have been found to regenerate, their ability has been studied at length.[4][21] In addition, lateral line hair cells, which have a mechanotransduction function, have been shown to regrow in organisms, such as the zebrafish.[22]. Researchers have identified a mammalian gene that normally acts as a molecular switch to block the regrowth of cochlear hair cells in adults.[23] The Rb1 gene encodes the retinoblastoma protein, which is a tumor suppressor. Rb stops cells from dividing by encouraging their exit from ...
PLoS Biol. 2013;11(6):e1001583. doi: 10.1371/journal.pbio.1001583. Epub 2013 Jun 11. Research Support, N.I.H., Extramural; Research Support, N.I.H., Intramural
The peripheral auditory system communicates with the central nervous system through synapses between the sensory cells and the spiral ganglion neurons. This sin...
The DNA methyltransferase (DNMT) inhibitor 5-azacytidine (5-aza) causes genomic demethylation to regulate gene expression. However, it remains unclear whether 5-aza affects gene expression and cell fate determination of stem cells. In this study, 5-aza was applied to mouse utricle sensory epithelia-derived progenitor cells (MUCs) to investigate whether 5-aza stimulated MUCs to become sensory hair cells. After treatment, MUCs increased expression of hair cell genes and proteins. The DNA methylation level (indicated by percentage of 5-methylcytosine) showed a 28.57% decrease after treatment, which causes significantly repressed DNMT1 protein expression and DNMT activity. Additionally, FM1-43 permeation assays indicated that the permeability of 5-aza-treated MUCs was similar to that of sensory hair cells, which may result from mechanotransduction channels. This study not only demonstrates a possible epigenetic approach to induce tissue specific stem/progenitor cells to become sensory hair cell-like cells,
Tiny hair cells in the inner ear play an outsized role.For balance, five separate patches of hair cells sense movement and tell the brain where the head is in space while translating the pull of gravity.For hearing, a five cell-wide ribbon of 16,000 hair cells spirals inside the cochlea, the snail-shaped structure where hair cells vibrate in response to sound waves. Every cycle of sound waves sends microscopic cilia on the tips of these cells back and forth, riding a trampoline of cells suspended between two fluid-filled spaces.
Following the loss of hair cells from the mammalian cochlea, the sensory epithelium repairs to close the lesions but no new hair cells arise and hearing impairment ensues. For any cell replacement strategy to be successful, the cellular environment o
Looking for hair cell? Find out information about hair cell. The basic sensory unit of the inner ear of vertebrates; a columnar, polarized structure with specialized cilia on the free surface Explanation of hair cell
Spiral ganglion cells (SGCs, the secondary sensory neurons making up the auditory nerve) are continuously firing cells in a healthy ear (they fall silent when the hair cells degenerate, leading to deafness). In fact, their base frequency in silence is pretty high. The only thing the hair cell input does is lowering, or elevating the threshold and hence affecting firing rate. During a sine wave stimulus (a pure tone), the stereocilia of the hair cells deflect in one phase, and inflect on the other. One phase hence depolarizes the SGC, the other hyperpolarizes it. This generates a near-perfect representation of the sine wave input at low frequencies. At high frequencies the SGCs may skip a phase or two, but because multiple SGCs are involved, the population code is still stochastically spot on.. Sound level is coded in spike rate, frequency is coded by a place-frequency map (Müller, 1996). The base of the cochlea codes high frequencies, the apex low frequencies. Hence, loudness is coded by every ...
The inner ear contains the auditory and vestibular organs, which are sensory neuroepithelia composed of mechanosensory hair cells and glia-like supporting cells. The mammalian auditory sensory epithelium, the organ of Corti, is responsible for transduction of sound stimuli into electrical signals for hearing function. Hair ...
A study of data collected from 2001-2004 estimated 35.4% of adults aged 40 and older have balance problems, with odds of dysfunction increasing significantly wi...
Foley, Shawn W., Gosai, Sager J., Wang, Dongxue, Selamoglu, Nur, Sollitti, Amelia C., Köster, Tino, Steffen, Alexander, Lyons, Eric, Daldal, Fevzi, Garcia, Benjamin A., Staiger, Dorothee, Deal, Roger B., and Gregory, Brian D. "A Global View of RNA-Protein Interactions Identifies Post-transcriptional Regulators of Root Hair Cell Fate". Developmental Cell 41.2 (2017): 204-220.e5 ...
This observation in mice suggests that a person who lacks one or both copies of Ink4d, or who has Ink4d genes that are not very active, might suffer progressive hair cell death and experience hearing loss, just as mice do, according to Neil Segil, Ph.D., a researcher at the House Ear Institute and a research associate professor at the University of Southern California Medical School (Los Angeles). Segil, a senior author of a paper reporting these results, published in the May 2003 issue of Nature Cell Biology, speculates that the lack of one or both Ink4d genes makes the person more susceptible to hair cell loss from a variety of different traumas, such as loud noise or certain medicines. According to this theory, trauma could stimulate hair cells to attempt to divide, and in turn, lead to apoptosis. This suggests that a person with a full set of Ink4d genes might be less susceptible to loud noise than a person with only half the set ...
st_jude_childrens_research_hospital_investigators_have_found_that_an_electrically_powered_amplification_mechanism_in_the_cochlea_of_the_ear_is_critical_to_the_acute_hearing_of_humans_and_other_mammals_the_findings_will_enable_better_understanding_of_how_hearing_loss_can_result_from_malfunction_of_this_amplification_machinery_due_to_genetic_mutation_or_overdose_of_drugs_such_as_aspirin
hair cell definition: A cell inside organ of Corti having good hairlike processes.; a sensory epithelial cellular contained in the organ of Corti
Free Online Library: Generation of hair cells: a monumental breakthrough.( , Editorial) by Ear, Nose and Throat Journal; Health, general Hearing loss Care and treatment Causes of
Using powerful electron microscopy techniques, Gleason and her colleagues confirmed previous findings in mice studies that showed abnormalities in the hair cells. The deaf zebra fish had fewer and shorter kinocilia as well as a reduced number of stereocillia. But the researchers also found that the tips of the stereocilia were much thinner than normal stereocilia and lacked a tethering protein that connects one stereocilium to the next. The findings, says Gleason, suggest that Tmie plays a bigger role in the transmission of sound than previously thought. "At the ultra-structural level, we specifically show that these mutant defects map to a very specific cog in the transduction machinery," says Gleason. "And thats exciting because we now have a clearer target for therapy. ...
Katie Kindt, Ph.D., Acting Chief Research Statement The section on Sensory Cell Development and Function investigates how discrete subcellular signals, such as Ca2+ influx and vesicle release, shape hair cell development, and how these signals are required for proper physiological function.
Keywords: Vestibular, type II locks cell, morphology, mammal, synapse, JAX:000654, JAX:000664, RGD: 737903, Abdominal_10013626, Abdominal_10015251, Abdominal_2282417, Abdominal_2068506, Abdominal_2068336, Abdominal_477329, Abdominal_177520, Abdominal_10175616, Abdominal_2113875, Abdominal_399431, Abdominal_2079751, Abdominal_2286684 Intro In mammals, five vestibular body organs INO-1001 in the internal hearing encode motions of the mind and therefore regulate look, body motions, and body alignment. The saccule and utricle possess a toned physical epithelium known as a macula, and they respond to linear mind speeding and mind tilt. The anterior, posterior, and horizontal ampullae possess a even more complexly formed physical epithelium known as a crista, and they identify mind rotation in a range of aeroplanes. Locks cells are the physical mechanoreceptors in these body organs. Directional deflections of lengthy microvilli (stereocilia) on the areas of locks cells travel actions possibilities in ...
Video created by 芝加哥大学 for the course 了解大脑:日常生活中的神经生物学. The vestibular system and gaze control give us so much but are grossly under appreciated. They are so fundamental that we discount them, assuming that they will always be there. When the ...
Video created by 芝加哥大学 for the course 了解大脑:日常生活中的神经生物学. The vestibular system and gaze control give us so much but are grossly under appreciated. They are so fundamental that we discount them, assuming that they will always be there. When the ...
Fascinatingly, the initial analysis of the human genome sequence revealed that, apparently, only a very small fraction of the DNA of our genome is encoding proteins. Scientists at first thought what is all this junk DNA about? or cant we just delete it?. Today, it has become clear that probably a major fraction of regulatory events taking place in a human cell might be governed by small RNAs, the so-called miRNAs. Among other functions, these appear responsible for making sure that a skin cell becomes a skin cell while a muscle, liver or hair cell differentiates to a muscle, liver or hair cell during development and all this although the genetic material (DNA) of all of these very different cell types is essentially identical. On top of that it seems that many cancer types are accompanied by or even result from a deregulated miRNA profile in the affected cell. Moreover, viruses have been discovered to bring along miRNAs to modify the target cells regulatory network leading to diseases ...
Regeneration of sensory hair cells in the mature avian inner ear was first described just over 20 years ago. Since then, it has been shown that many other non-mammalian species either continually produce new hair cells or regenerate them in response to trauma. However, mammals exhibit limited hair cell regeneration, particularly in the auditory epithelium. In birds and other non-mammals, regenerated hair cells arise from adjacent non-sensory (supporting) cells. Hair cell regeneration was initially described as a proliferative response whereby supporting cells re-enter the mitotic cycle, forming daughter cells that differentiate into either hair cells or supporting cells and thereby restore cytoarchitecture and function in the sensory epithelium. However, further analyses of the avian auditory epithelium (and amphibian vestibular epithelium) revealed a second regenerative mechanism, direct transdifferentiation, during which supporting cells change their gene expression and convert into hair cells without
TY - JOUR. T1 - Aminoglycoside-Induced Hair Cell Death of Inner Ear Organs Causes Functional Deficits in Adult Zebrafish (Danio rerio). AU - Uribe, Phillip M.. AU - Sun, Huifang. AU - Wang, Kevin. AU - Asuncion, James D.. AU - Wang, Qi. AU - Chen, Chien Wei. AU - Steyger, Peter S.. AU - Smith, Michael E.. AU - Matsui, Jonathan I.. PY - 2013/3/22. Y1 - 2013/3/22. N2 - Aminoglycoside antibiotics, like gentamicin, kill inner ear sensory hair cells in a variety of species including chickens, mice, and humans. The zebrafish (Danio rerio) has been used to study hair cell cytotoxicity in the lateral line organs of larval and adult animals. Little is known about whether aminoglycosides kill the hair cells within the inner ear of adult zebrafish. We report here the ototoxic effects of gentamicin on hair cells in the saccule, the putative hearing organ, and utricle of zebrafish. First, adult zebrafish received a single 30 mg/kg intraperitoneal injection of fluorescently-tagged gentamicin (GTTR) to ...
The goal of Ruben Stepanyans lab The goal of the labs research is to study hair cell mechanosensitivity and calcium homeostasis in normal and pathological conditions. Mechanosensitivity of hair cells is necessary for our hearing while calcium is an essential modulator of mechano-electrical transduction. During excessively loud sounds and noise a substantial amount of calcium ions enter hair cells through mechanotransduction channels. Therefore it is important for hair cells to be able to buffer and extrude excessive Ca2; compromised calcium balance is a significant factor leading to hair cell death. Outer hair cells, one of the two types of auditory hair cell in mammalian cochlea, rely on mobile calcium buffers and plasma membrane calcium pumps to regulate calcium levels. A particular interest of the lab is establishing the exact mechanism by which sounds and noise lead to calcium overload in basal, high frequency, outer hair cells. Generally, hearing loss occurs at the higher frequencies ...
During this work we investigated organization, molecular composition and function of hair cell ribbon synapses. We demonstrated RIBEYE, Bassoon and Piccolo to be components of IHC synaptic ribbons. In the present study we showed that anchoring of IHC ribbons is impaired in mouse mutants for the presynaptic scaffolding protein Bassoon. The lack of active, zone-anchored synaptic ribbons reduced the presynaptic readily releasable vesicle pool, and impaired synchronous auditory signalling as revealed by recordings of exocytic IHC capacitance changes and sound-evoked activation of spiral ganglion neurons. Both exocytosis of the hair cell releasable vesicle pool and the number of synchronously activated spiral ganglion neurons co-varied with the number of anchored ribbons during development. Interestingly, ribbon-deficient IHCs were still capable of sustained exocytosis with normal Ca2+-dependence. Endocytic membrane retrieval was intact, but an accumulation of tubular and cisternal membrane profiles ...
The site of transduction is in the organ of Corti (spiral organ). It is composed of hair cells held in place above the basilar membrane like flowers projecting up from soil, with their exposed short, hair-like stereocilia contacting or embedded in the tectorial membrane above them. The inner hair cells are the primary auditory receptors and exist in a single row, numbering approximately 3,500. The stereocilia from inner hair cells extend into small dimples on the tectorial membranes lower surface. The outer hair cells are arranged in three or four rows. They number approximately 12,000, and they function to fine tune incoming sound waves. The longer stereocilia that project from the outer hair cells actually attach to the tectorial membrane. All of the stereocilia are mechanoreceptors, and when bent by vibrations they respond by opening a gated ion channel (refer to Figure 17.2). As a result, the hair cell membrane is depolarized, and a signal is transmitted to the chochlear nerve. Intensity ...
The sensory epithelia of the inner ear are composed of mechanosensory hair cells and supporting cells, organised into a checkerboard-like pattern. Hair cells are essential for hearing and their loss after exposure to excessive noise (watch your iPods!) and during ageing is the main cause of deafness in humans. This is because in the mammalian auditory organ, the full complement of hair cells is produced during embryonic development. In contrast, reptiles, fish and birds can regenerate their hair cells throughout adult life. In these species, the supporting cells act as tissue stem cells following hair cell loss. Supporting cells can i) re-enter the cell cycle to produce new hair cells and supporting cells, or ii) convert directly into replacement hair cells. What are the molecular signals and genetic networks controlling hair cell formation and regeneration? And could these be manipulated to promote regenerative processes in the mammalian ear? Research in my lab aims to provide some answers ...
Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, ...
Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, ...
Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, ...
Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, ...
Inner ear hair cells convert the mechanical stimuli of sound, gravity, and head movement into electrical signals. This mechanotransduction process is initiated by opening of cation channels near the tips of hair cell stereocilia. Since the identity of these ion channels is unknown, and mutations in the gene encoding transmembrane channel-like 1 (TMC1) cause hearing loss without vestibular dysfunction in both mice and humans, we investigated the contribution of Tmc1 and the closely related Tmc2 to mechanotransduction in mice. We found that Tmc1 and Tmc2 were expressed in mouse vestibular and cochlear hair cells and that GFP-tagged TMC proteins localized near stereocilia tips. Tmc2 expression was transient in early postnatal mouse cochlear hair cells but persisted in vestibular hair cells. While mice with a targeted deletion of Tmc1 (Tmc1Δ mice) were deaf and those with a deletion of Tmc2 (Tmc2Δ mice) were phenotypically normal, Tmc1ΔTmc2Δ mice had profound vestibular dysfunction, deafness, ...