Otoacoustic emissions reveal the micromechanical role of organ-of-Corti cytoarchitecture in cochlear amplification.

The intricate, crystalline cytoarchitecture of the mammalian organ of Corti presumably plays an important role in cochlear amplification. As currently understood, the oblique, Y-shaped arrangement of the outer hair cells (OHCs) and phalangeal processes of the Deiters cells serves to create differential "push-pull" forces that drive the motion of the basilar membrane via the spatial feedforward and/or feedbackward of OHC forces. In concert with the cochlear traveling wave, the longitudinal separation between OHC sensing and forcing creates phase shifts that yield a form of negative damping, amplifying waves as they propagate. Unlike active forces that arise and act locally, push-pull forces are inherently directional-whereas forward-traveling waves are boosted, reverse-traveling waves are squelched. Despite their attractions, models based on push-pull amplification must contend with otoacoustic emissions (OAEs), whose existence implies that amplified energy escapes from the inner ear via mechanisms involving reverse traveling waves. We analyze hybrid local/push-pull models to determine the constraints that reflection-source OAEs place on the directionality of cochlear wave propagation. By implementing a special force-mixing control knob, we vary the mix of local and push-pull forces while leaving the forward-traveling wave unchanged. Consistency with stimulus-frequency OAEs requires that the active forces underlying cochlear wave amplification be primarily local in character, contradicting the prevailing view. By requiring that the oblique cytoarchitecture produce predominantly local forces, we reinterpret the functional role of the Y-shaped geometry, proposing that it serves not as a push-pull amplifier, but as a mechanical funnel that spatially integrates local OHC forces.

Optogenetics Reveals Roles for Supporting Cells in Force Transmission to and From Outer Hair Cells in the Mouse Cochlea.

Outer hair cells (OHCs) of the organ of Corti (OoC), acting as bidirectional cellular mechanoelectrical transducers, generate, receive, and exchange forces with other major elements of the cochlear partition, including the sensory inner hair cells (IHCs). Force exchange is mediated via a supporting cell scaffold, including Deiters' (DC) and outer pillar cells (OPC), to enable the sensitivity and exquisite frequency selectivity of the mammalian cochlea and to transmit its responses to the auditory nerve. To selectively activate DCs and OPCs in male and female mice, we conditionally expressed in them a hyperpolarizing halorhodopsin (HOP), a light-gated inward chloride ion pump, and measured extracellular receptor potentials (ERPs) and their DC component (ERPDCs) from the cortilymph, which fills the OoC fluid spaces, and compared the responses with similar potentials from HOP-/- littermates. The compound action potentials (CAP) of the auditory nerve were measured as an indication of IHC activity and transmission of cochlear responses to the CNS. HOP light-activated hyperpolarization of DCs and OPCs suppressed cochlear amplification through changing the timing of its feedback, altered basilar membrane (BM) responses to tones at all measured levels and frequencies, and reduced IHC excitation. HOP activation findings reported here complement recent studies that revealed channelrhodopsin activation depolarized DCs and OPCs and effectively bypassed, rather than blocked, the control of OHC mechanical and electrical responses to sound and their contribution to timed and directed electromechanical feedback to the mammalian cochlea. Moreover, our findings identify DCs and OPCs as potential targets for the treatment of noise-induced hearing loss.

On the Tonotopy of the Low-Frequency Region of the Cochlea.

It is generally assumed that frequency selectivity varies along the cochlea. For example, at the base of the cochlea, which is a region sensitive to high-frequency sounds, the best frequency of a cochlear location increases toward the most basal end, that is, near the stapes. Response phases also vary along cochlear locations. At any given frequency, there is a decrease in phase lag toward the stapes. This tonotopic arrangement in the cochlea was originally described by Georg von Békésy in a seminal series of experiments on human cadavers and has been confirmed in more recent works on live laboratory animals. Nonetheless, our knowledge of tonotopy at the apex of the cochlea remains incomplete in animals with low-frequency hearing, which is relevant to human speech. The results of our experiments on guinea pig, gerbil, and chinchilla cochleas, regardless of the sex of the animal, show that responses to sound differ at locations across the apex in a pattern consistent with previous studies of the base of the cochlea.SIGNIFICANCE STATEMENT Tonotopy is an important property of the auditory system that has been shown to exist in many auditory centers. In fact, most auditory implants work on the assumption of its existence by assigning different frequencies to different stimulating electrodes based on their location. At the level of the basilar membrane in the cochlea, a tonotopic arrangement implies that high-frequency stimuli evoke largest displacements at the base, near the ossicles, and low-frequency sounds have their greatest effects at the apex. Although tonotopy has been confirmed at the base of the cochlea on live animals at the apex of the cochlea, however, it has been less studied. Here, we show that a tonotopic arrangement does exist at the apex of the cochlea.

Lrrn1 Regulates Medial Boundary Formation in the Developing Mouse Organ of Corti.

One of the most striking aspects of the sensory epithelium of the mammalian cochlea, the organ of Corti (OC), is the presence of precise boundaries between sensory and nonsensory cells at its medial and lateral edges. A particular example of this precision is the single row of inner hair cells (IHCs) and associated supporting cells along the medial (neural) boundary. Despite the regularity of this boundary, the developmental processes and genetic factors that contribute to its specification are poorly understood. In this study we demonstrate that Leucine Rich Repeat Neuronal 1 (Lrrn1), which codes for a single-pass, transmembrane protein, is expressed before the development of the mouse organ of Corti in the row of cells that will form its medial border. Deletion of Lrrn1 in mice of mixed sex leads to disruptions in boundary formation that manifest as ectopic inner hair cells and supporting cells. Genetic and pharmacological manipulations demonstrate that Lrrn1 interacts with the Notch signaling pathway and strongly suggest that Lrrn1 normally acts to enhance Notch signaling across the medial boundary. This interaction is required to promote formation of the row of inner hair cells and suppress the conversion of adjacent nonsensory cells into hair cells and supporting cells. These results identify Lrrn1 as an important regulator of boundary formation and cellular patterning during development of the organ of Corti.SIGNIFICANCE STATEMENT Patterning of the developing mammalian cochlea into distinct sensory and nonsensory regions and the specification of multiple different cell fates within those regions are critical for proper auditory function. Here, we report that the transmembrane protein Leucine Rich Repeat Neuronal 1 (LRRN1) is expressed along the sharp medial boundary between the single row of mechanosensory inner hair cells (IHCs) and adjacent nonsensory cells. Formation of this boundary is mediated in part by Notch signaling, and loss of Lrrn1 leads to disruptions in boundary formation similar to those caused by a reduction in Notch activity, suggesting that LRRN1 likely acts to enhance Notch signaling. Greater understanding of sensory/nonsensory cell fate decisions in the cochlea will help inform the development of regenerative strategies aimed at restoring auditory function.

Deiters Cells Act as Mechanical Equalizers for Outer Hair Cells.

The outer hair cells in the mammalian cochlea are cellular actuators essential for sensitive hearing. The geometry and stiffness of the structural scaffold surrounding the outer hair cells will determine how the active cells shape mammalian hearing by modulating the organ of Corti (OoC) vibrations. Specifically, the tectorial membrane and the Deiters cell are mechanically in series with the hair bundle and soma, respectively, of the outer hair cell. Their mechanical properties and anatomic arrangement must determine the relative motion among different OoC structures. We measured the OoC mechanics in the cochleas acutely excised from young gerbils of both sexes at a resolution fine enough to distinguish the displacement of individual cells. A three-dimensional finite element model of fully deformable OoC was exploited to analyze the measured data in detail. As a means to verify the computer model, the basilar membrane deformations because of static and dynamic stimulations were measured and simulated. Two stiffness ratios have been identified that are critical to understand cochlear physics, which are the stiffness of the tectorial membrane with respect to the hair bundle and the stiffness of the Deiters cell with respect to the outer hair cell body. Our measurements suggest that the Deiters cells act like a mechanical equalizer so that the outer hair cells are constrained neither too rigidly nor too weakly.SIGNIFICANCE STATEMENT Mammals can detect faint sounds thanks to the action of mammalian-specific receptor cells called the outer hair cells. It is getting clearer that understanding the interactions between the outer hair cells and their surrounding structures such as the tectorial membrane and the Deiters cell is critical to resolve standing debates. Depending on theories, the stiffness of those two structures ranges from negligible to rigid. Because of their perceived importance, their properties have been measured in previous studies. However, nearly all existing data were obtained ex situ (after they were detached from the outer hair cells), which obscures their interaction with the outer hair cells. We quantified the mechanical properties of the tectorial membrane and the Deiters cell in situ.

Development of the cochlea.

The cochlea, a coiled structure located in the ventral region of the inner ear, acts as the primary structure for the perception of sound. Along the length of the cochlear spiral is the organ of Corti, a highly derived and rigorously patterned sensory epithelium that acts to convert auditory stimuli into neural impulses. The development of the organ of Corti requires a series of inductive events that specify unique cellular characteristics and axial identities along its three major axes. Here, we review recent studies of the cellular and molecular processes regulating several aspects of cochlear development, such as axial patterning, cochlear outgrowth and cellular differentiation. We highlight how the precise coordination of multiple signaling pathways is required for the successful formation of a complete organ of Corti.

Organ of Corti size is governed by Yap/Tead-mediated progenitor self-renewal.

Precise control of organ growth and patterning is executed through a balanced regulation of progenitor self-renewal and differentiation. In the auditory sensory epithelium-the organ of Corti-progenitor cells exit the cell cycle in a coordinated wave between E12.5 and E14.5 before the initiation of sensory receptor cell differentiation, making it a unique system for studying the molecular mechanisms controlling the switch between proliferation and differentiation. Here we identify the Yap/Tead complex as a key regulator of the self-renewal gene network in organ of Corti progenitor cells. We show that Tead transcription factors bind directly to the putative regulatory elements of many stemness- and cell cycle-related genes. We also show that the Tead coactivator protein, Yap, is degraded specifically in the Sox2-positive domain of the cochlear duct, resulting in down-regulation of Tead gene targets. Further, conditional loss of the Yap gene in the inner ear results in the formation of significantly smaller auditory and vestibular sensory epithelia, while conditional overexpression of a constitutively active version of Yap, Yap5SA, is sufficient to prevent cell cycle exit and to prolong sensory tissue growth. We also show that viral gene delivery of Yap5SA in the postnatal inner ear sensory epithelia in vivo drives cell cycle reentry after hair cell loss. Taken together, these data highlight the key role of the Yap/Tead transcription factor complex in maintaining inner ear progenitors during development, and suggest new strategies to induce sensory cell regeneration.

The Dual Roles of Triiodothyronine in Regulating the Morphology of Hair Cells and Supporting Cells during Critical Periods of Mouse Cochlear Development.

Clinically, thyroid-related diseases such as endemic iodine deficiency and congenital hypothyroidism are associated with hearing loss, suggesting that thyroid hormones are essential for the development of normal hearing. Triiodothyronine (T3) is the main active form of thyroid hormone and its effect on the remodeling of the organ of Corti remain unclear. This study aims to explore the effect and mechanism of T3 on the remodeling of the organ of Corti and supporting cells development during early development. In this study, mice treated with T3 at postnatal (P) day 0 or P1 showed severe hearing loss with disordered stereocilia of the outer hair cells (OHCs) and impaired function of mechanoelectrical transduction of OHCs. In addition, we found that treatment with T3 at P0 or P1 resulted in the overproduction of Deiter-like cells. Compared with the control group, the transcription levels of Sox2 and notch pathway-related genes in the cochlea of the T3 group were significantly downregulated. Furthermore, Sox2-haploinsufficient mice treated with T3 not only showed excess numbers of Deiter-like cells but also a large number of ectopic outer pillar cells (OPCs). Our study provides new evidence for the dual roles of T3 in regulating both hair cells and supporting cell development, suggesting that it is possible to increase the reserve of supporting cells.

Immunohistochemistry Reveals TRPC Channels in the Human Hearing Organ-A Novel CT-Guided Approach to the Cochlea.

TRPC channels are critical players in cochlear hair cells and sensory neurons, as demonstrated in animal experiments. However, evidence for TRPC expression in the human cochlea is still lacking. This reflects the logistic and practical difficulties in obtaining human cochleae. The purpose of this study was to detect TRPC6, TRPC5 and TRPC3 in the human cochlea. Temporal bone pairs were excised from ten body donors, and the inner ear was first assessed based on computed tomography scans. Decalcification was then performed using 20% EDTA solutions. Immunohistochemistry with knockout-tested antibodies followed. The organ of Corti, the stria vascularis, the spiral lamina, spiral ganglion neurons and cochlear nerves were specifically stained. This unique report of TRPC channels in the human cochlea supports the hypothesis of the potentially critical role of TRPC channels in human cochlear health and disease which has been suggested in previous rodent experiments.

Active role of glia-like supporting cells in the organ of Corti: Membrane proteins and their roles in hearing.

The organ of Corti, located in the cochlea in the inner ear, is one of the major sensory organs involved in hearing. The organ of Corti consists of hair cells, glia-like supporting cells, and the cochlear nerve, which work in harmony to receive sound from the outer ear and transmit auditory signals to the cochlear nucleus in the auditory ascending pathway. In this process, maintenance of the endocochlear potential, with a high potassium gradient and clearance of electrolytes and biochemicals in the inner ear, is critical for normal sound transduction. There is an emerging need for a thorough understanding of each cell type involved in this process to understand the sophisticated mechanisms of the organ of Corti. Hair cells have long been thought to be active, playing a primary role in the cochlea in actively detecting and transmitting signals. In contrast, supporting cells are thought to be silent and function to support hair cells. However, growing lines of evidence regarding the membrane proteins that mediate ionic movement in supporting cells have demonstrated that supporting cells are not silent, but actively play important roles in normal signal transduction. In this review, we summarize studies that characterize diverse membrane proteins according to the supporting cell subtypes involved in cochlear physiology and hearing. This review contributes to a better understanding of supporting cell functions and facilitates the development of potential therapeutic tools for hearing loss.

Genomic architecture of Shh-dependent cochlear morphogenesis.

The mammalian cochlea develops from a ventral outgrowth of the otic vesicle in response to Shh signaling. Mouse embryos lacking Shh or its essential signal transduction components display cochlear agenesis; however, a detailed understanding of the transcriptional network mediating this process is unclear. Here, we describe an integrated genomic approach to identify Shh-dependent genes and associated regulatory sequences that promote cochlear duct morphogenesis. A comparative transcriptome analysis of otic vesicles from mouse mutants exhibiting loss (Smoecko ) and gain (Shh-P1) of Shh signaling reveal a set of Shh-responsive genes partitioned into four expression categories in the ventral half of the otic vesicle. This target gene classification scheme provides novel insight into several unanticipated roles for Shh, including priming the cochlear epithelium for subsequent sensory development. We also mapped regions of open chromatin in the inner ear by ATAC-seq that, in combination with Gli2 ChIP-seq, identified inner ear enhancers in the vicinity of Shh-responsive genes. These datasets are useful entry points for deciphering Shh-dependent regulatory mechanisms involved in cochlear duct morphogenesis and establishment of its constituent cell types.

Cochlear amplification and tuning depend on the cellular arrangement within the organ of Corti.

The field of cochlear mechanics has been undergoing a revolution due to recent findings made possible by advancements in measurement techniques. While it has long been assumed that basilar-membrane (BM) motion is the most important determinant of sound transduction by the inner hair cells (IHCs), it turns out that other parts of the sensory epithelium closer to the IHCs, such as the reticular lamina (RL), move with significantly greater amplitude for weaker sounds. It has not been established how these findings are related to the complex cytoarchitecture of the organ of Corti between the BM and RL, which is composed of a lattice of asymmetric Y-shaped elements, each consisting of a basally slanted outer hair cell (OHC), an apically slanted phalangeal process (PhP), and a supporting Deiters' cell (DC). Here, a computational model of the mouse cochlea supports the hypothesis that the OHC micromotors require this Y-shaped geometry for their contribution to the exquisite sensitivity and frequency selectivity of the mammalian cochlea. By varying only the OHC gain parameter, the model can reproduce measurements of BM and RL gain and tuning for a variety of input sound levels. Malformations such as reversing the orientations of the OHCs and PhPs or removing the PhPs altogether greatly reduce the effectiveness of the OHC motors. These results imply that the DCs and PhPs must be properly accounted for in emerging OHC regeneration therapies.

Association of Conductive Hearing Loss with the Structural Changes in the Organ of Corti.

OBJECTIVE: The aim of the study was to evaluate the association of conductive hearing loss (CHL) with the structural changes in the organ of Corti. METHODS: Twenty ears of 10 healthy adult Wistar albino rats were included in the study. The right ears (n = 10) of the animals served as controls (group 1), and no surgical intervention was performed in these ears. A tympanic membrane perforation without annulus removal was performed under operative microscope on the left ears (n = 5) in 5 of 10 animals (group 2). A tympanic membrane perforation with annulus removal was performed under operative microscope on the left ears (n = 5) of the remaining 5 animals (group 3). Auditory brainstem response testing was performed in the animals before the interventions. After 3 months, the animals were sacrificed, their temporal bones were removed, and inner ears were investigated using scanning electron microscopy (SEM). The organ of Corti was evaluated from the cochlear base to apex in the modiolar axis, and the parameters were scored semiquantitatively. RESULTS: In group 1, the pre- and post-intervention hearing thresholds were similar (p > 0.05). In group 2, a hearing decrease of at least 5 dB was encountered in all test frequencies (p > 0.05). In group 3, at the frequency range of 2-32 kHz, there was a significant hearing loss after 3 months (p < 0.01). After 3 months, the hearing thresholds in group 2 and 3 were higher than group 1 (p < 0.01). The hearing threshold in group 3 was higher than group 2 (p < 0.01). On SEM evaluation, the general cell morphology and stereocilia of the outer hair cells were preserved in all segments of the cochlea in group 1 with a mean SEM score of 0.2. There was segmental degeneration in the general cell morphology and outer hair cells in group 2 with a mean SEM score of 2.2. There was widespread degeneration in the general cell morphology and outer hair cells in group 3 with a mean SEM score of 3.2. The SEM scores of group 2 and 3 were significantly higher than group 1 (p < 0.05). The SEM scores of group 3 were significantly higher than group 2 (p < 0.05). CONCLUSION: CHL may be associated with an inner ear damage. The severity of damage appears to be associated with severity and duration of CHL. Early correction of CHL is advocated in order to reverse or prevent progression of the inner ear damage, which will enhance the success rates of hearing restoration surgeries. Subjective differences and compliance of the hearing aid users may be due to the impact of CHL on inner ear structures.

[Influence of cochlear parameters on the current practice in cochlear implantation : Development of a concept for personalized medicine. German version]. / Einfluss cochleärer Parameter auf die aktuelle Cochleaimplantatversorgung : Entwicklung eines Konzepts für die personalisierte Medizin.

Since the introduction of cochlear implants into clinical routine, the interest in measuring cochlear parameters, particularly the cochlear duct length (CDL) has increased, since these can have an influence on the correct selection of the electrode. On the one hand, coverage of an optimal frequency band is relevant for a good audiological result, and on the other hand, cochlear trauma due to too deep insertion or displacement of the electrode must be avoided. Cochlear implants stimulate the spiral ganglion cells (SGC). The number of SGC and particularly their distribution can also have an influence on the function of a cochlear implant. In addition, the frequency assignment of each electrode contact can play a decisive role in the postoperative success, since the frequency distribution of the human cochlea with varying CDL shows substantial interindividual differences. The aim of this work is to provide an overview of the methods used to determine the cochlear parameters as well as of relevant studies on the CDL, the number and distribution of SGZ, and the frequency assignment of electrode contacts. Based on this, a concept for individualized cochlear implantation will be presented. In summary, this work should help to promote individualized medicine in the field of cochlear implants in the future, in order to overcome current limitations and optimize audiological outcomes.

Influence of cochlear parameters on the current practice in cochlear implantation : Development of a concept for personalized medicine.

Since the introduction of cochlear implants into clinical routine, the interest in measuring cochlear parameters, particularly the cochlear duct length (CDL) has increased, since these can have an influence on the correct selection of the electrode. On the one hand, coverage of an optimal frequency band is relevant for a good audiological result, and on the other hand, cochlear trauma due to too deep insertion or displacement of the electrode must be avoided. Cochlear implants stimulate the spiral ganglion cells (SGC). The number of SGC and particularly their distribution can also have an influence on the function of a cochlear implant. In addition, the frequency assignment of each electrode contact can play a decisive role in the postoperative success, since the frequency distribution of the human cochlea with varying CDL shows substantial interindividual differences. The aim of this work is to provide an overview of the methods used to determine the cochlear parameters as well as of relevant studies on the CDL, the number and distribution of SGZ, and the frequency assignment of electrode contacts. Based on this, a concept for individualized cochlear implantation will be presented. In summary, this work should help to promote individualized medicine in the field of cochlear implants in the future, in order to overcome current limitations and optimize audiological outcomes.

Do as I say, Not(ch) as I do: Lateral control of cell fate.

Breaking symmetry in populations of uniform cells, to induce adoption of an alternative cell fate, is an essential developmental mechanism. Similarly, domain and boundary establishment are crucial steps to forming organs during development. Notch signaling is a pathway ideally suited to mediating precise patterning cues, as both receptors and ligands are membrane-bound and can thus act as a precise switch to toggle cell fates on or off. Fine-tuning of signaling by positive or negative feedback mechanisms dictate whether signaling results in lateral induction or lateral inhibition, respectively, allowing Notch to either induce entire regions of cell specification, or dictate binary fate choices. Furthermore, pathway activity is modulated by Fringe modification of receptors or ligands, co-expression of receptors with ligands, mode of ligand presentation, and cell surface area in contact. In this review, we describe how Notch signaling is fine-tuned to mediate lateral induction or lateral inhibition cues, and discuss examples from C.elegans, D. melanogaster and M. musculus. Identifying the cellular machinery dictating the choice between lateral induction and lateral inhibition highlights the versatility of the Notch signaling pathway in development.

Differential deletion of GDNF in the auditory system leads to altered sound responsiveness.

Glial-derived neurotrophic factor (GDNF) has been proposed as a potent neurotrophic factor with the potential to cure neurodegenerative diseases. In the cochlea, GDNF has been detected in auditory neurons and sensory receptor cells and its expression is upregulated upon trauma. Moreover, the application of GDNF in different animal models of deafness has shown its capacity to prevent hearing loss and promoted its future use in therapeutic trials in humans. In the present study we have examined the endogenous requirement of GDNF during auditory development in mice. Using a lacZ knockin allele we have confirmed the expression of GDNF in the cochlea including its sensory regions during development. Global inactivation of GDNF throughout the hearing system using a Foxg1-Cre line causes perinatal lethality but reveals no apparent defects during formation of the cochlea. Using TrkC-Cre and Atoh1-Cre lines, we were able to generate viable mutants lacking GDNF in auditory neurons or both auditory neurons and sensory hair cells. These mutants show normal frequency-dependent auditory thresholds. However, mechanoelectrical response properties of outer hair cells (OHCs) in TrkC-Cre GDNF mutants are altered at low thresholds. Furthermore, auditory brainstem wave analysis shows an abnormal increase of wave I. On the other hand, Atoh1-Cre GDNF mutants show normal OHC function but their auditory brainstem wave pattern is reduced at the levels of wave I, III and IV. These results show that GDNF expression during the development is required to maintain functional hearing at different levels of the auditory system.

Telmisartan Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro.

BACKGROUND: Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. OBJECTIVES: The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. METHODS: Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. RESULTS: Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. CONCLUSIONS: We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss.

Notch Signalling: The Multitask Manager of Inner Ear Development and Regeneration.

Notch signalling is a major regulator of cell fate decisions and tissue patterning in metazoans. It is best known for its role in lateral inhibition, whereby Notch mediates competitive interactions between cells to limit adoption of a given developmental fate. However, it can also function by lateral induction, a cooperative mode of action that was originally described during the patterning of the Drosophila wing disc and creates boundaries or domains of cells of the same character. In this chapter, we introduce these two signalling modes and explain how they contribute to distinct aspects of the development and regeneration of the vertebrate inner ear, the organ responsible for the perception of sound and head movements. We discuss some of the factors that could influence the context-specific outcomes of Notch signalling in the inner ear and the ongoing efforts to target this pathway for the treatment of hearing loss and vestibular dysfunction.

Selection of cell fate in the organ of Corti involves the integration of Hes/Hey signaling at the Atoh1 promoter.

Determination of cell fate within the prosensory domain of the developing cochlear duct relies on the temporal and spatial regulation of the bHLH transcription factor Atoh1. Auditory hair cells and supporting cells arise in a wave of differentiation that patterns them into discrete rows mediated by Notch-dependent lateral inhibition. However, the mechanism responsible for selecting sensory cells from within the prosensory competence domain remains poorly understood. We show in mice that rather than being upregulated in rows of cells, Atoh1 is subject to transcriptional activation in groups of prosensory cells, and that highly conserved sites for Hes/Hey repressor binding in the Atoh1 promoter are needed to select the hair cell and supporting cell fate. During perinatal supporting cell transdifferentiation, which is a model of hair cell regeneration, we show that derepression is sufficient to induce Atoh1 expression, suggesting a mechanism for priming the 3' Atoh1 autoregulatory enhancer needed for hair cell expression.