scholarly journals β-Catenin is required for radial cell patterning and identity in the developing mouse cochlea

2019 ◽  
Vol 116 (42) ◽  
pp. 21054-21060 ◽  
Author(s):  
Lina Jansson ◽  
Michael Ebeid ◽  
Jessica W. Shen ◽  
Tara E. Mokhtari ◽  
Lee A. Quiruz ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Hair Cell ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Outer Hair Cells ◽  
Supporting Cells ◽  
Aberrant Expression ◽  
Cell Identity ◽  
Pillar Cell ◽  
Radial Patterning

Development of multicellular organs requires the coordination of cell differentiation and patterning. Critical for sound detection, the mammalian organ of Corti contains functional units arranged tonotopically along the cochlear turns. Each unit consists of sensory hair cells intercalated by nonsensory supporting cells, both specified and radially patterned with exquisite precision during embryonic development. However, how cell identity and radial patterning are jointly controlled is poorly understood. Here we show that β-catenin is required for specification of hair cell and supporting cell subtypes and radial patterning of the cochlea in vivo. In 2 mouse models of conditional β-catenin deletion, early specification of Myosin7-expressing hair cells and Prox1-positive supporting cells was preserved. While β-catenin-deficient cochleae expressed FGF8 and FGFR3, both of which are essential for pillar cell specification, the radial patterning of organ of Corti was disrupted, revealed by aberrant expression of cadherins and the pillar cell markers P75 and Lgr6. Moreover, β-catenin ablation caused duplication of FGF8-positive inner hair cells and reduction of outer hair cells without affecting the overall hair cell density. In contrast, in another transgenic model with suppressed transcriptional activity of β-catenin but preserved cell adhesion function, both specification and radial patterning of the organ of Corti were intact. Our study reveals specific functions of β-catenin in governing cell identity and patterning mediated through cell adhesion in the developing cochlea.

scholarly journals Cochlear progenitor number is controlled through mesenchymal FGF receptor signaling

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Sung-Ho Huh ◽  
Mark E Warchol ◽  
David M Ornitz
Keyword(s):  
Growth Factors ◽  
Hair Cells ◽  
Fibroblast Growth Factors ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Feedback Mechanism ◽  
Outer Hair Cells ◽  
Fibroblast Growth ◽  
Supporting Cells ◽  
Fgf Receptor

The sensory and supporting cells (SCs) of the organ of Corti are derived from a limited number of progenitors. The mechanisms that regulate the number of sensory progenitors are not known. Here, we show that Fibroblast Growth Factors (FGF) 9 and 20, which are expressed in the non-sensory (Fgf9) and sensory (Fgf20) epithelium during otic development, regulate the number of cochlear progenitors. We further demonstrate that Fgf receptor (Fgfr) 1 signaling within the developing sensory epithelium is required for the differentiation of outer hair cells and SCs, while mesenchymal FGFRs regulate the size of the sensory progenitor population and the overall cochlear length. In addition, ectopic FGFR activation in mesenchyme was sufficient to increase sensory progenitor proliferation and cochlear length. These data define a feedback mechanism, originating from epithelial FGF ligands and mediated through periotic mesenchyme that controls the number of sensory progenitors and the length of the cochlea.

scholarly journals Aquaporin-6 Expression in the Cochlear Sensory Epithelium Is Downregulated by Salicylates

2010 ◽  
Vol 2010 ◽  
pp. 1-8 ◽  
Author(s):  
Paola Perin ◽  
Simona Tritto ◽  
Laura Botta ◽  
Jacopo Maria Fontana ◽  
Giulia Gastaldi ◽  
...  
Keyword(s):  
Inner Ear ◽  
Expression Pattern ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Outer Hair Cells ◽  
Rt Pcr ◽  
Supporting Cells ◽  
Sensory Epithelia ◽  
Mechanical Compliance

We characterize the expression pattern of aquaporin-6 in the mouse inner ear by RT-PCR and immunohistochemistry. Our data show that in the inner ear aquaporin-6 is expressed, in both vestibular and acoustic sensory epithelia, by the supporting cells directly contacting hair cells. In particular, in the Organ of Corti, expression was strongest in Deiters' cells, which provide both a mechanical link between outer hair cells (OHCs) and the Organ of Corti, and an entry point for ion recycle pathways. Since aquaporin-6 is permeable to both water and anions, these results suggest its possible involvement in regulating OHC motility, directly through modulation of water and chloride flow or by changing mechanical compliance in Deiters' cells. In further support of this role, treating mice with salicylates, which impair OHC electromotility, dramatically reduced aquaporin-6 expression in the inner ear epithelia but not in control tissues, suggesting a role for this protein in modulating OHCs' responses.

Epithelial supporting cells can differentiate into outer hair cells and Deiters' cells in the cultured organ of Corti

2002 ◽  
Vol 59 (10) ◽  
pp. 1744-1757 ◽  
Author(s):  
B. Malgrange ◽  
M. Thiry ◽  
T. R. Van de Water ◽  
L. Nguyen ◽  
G. Moonen ◽  
...  
Keyword(s):  
Hair Cells ◽  
Organ Of Corti ◽  
Outer Hair Cells ◽  
Supporting Cells

scholarly journals Sox2 and FGF20 interact to regulate organ of Corti hair cell and supporting cell development in a spatially-graded manner

2018 ◽  
Author(s):  
Lu M. Yang ◽  
Kathryn S.E. Cheah ◽  
Sung-Ho Huh ◽  
David M. Ornitz
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Hair Cells ◽  
Genetic Interaction ◽  
Organ Of Corti ◽  
Supporting Cell ◽  
Cell Development ◽  
Supporting Cells ◽  
Outer Compartment ◽  
Mouse Organ

AbstractThe mouse organ of Corti develops in two steps: progenitor specification and differentiation. Fibroblast Growth Factor (FGF) signaling is important in this developmental pathway, as deletion of FGF receptor 1 (Fgfr1) or its ligand, Fgf20, leads to the loss of hair cells and supporting cells from the organ of Corti. However, whether FGF20-FGFR1 signaling is required during specification or differentiation, and how it interacts with the transcription factor Sox2, also important for hair cell and supporting cell development, has been a topic of debate. Here, we show that while FGF20-FGFR1 signaling functions during progenitor differentiation, FGFR1 has an FGF20-independent, Sox2-dependent role in specification. We also show that a combination of reduction in Sox2 expression and Fgf20 deletion recapitulates the Fgfr1-deletion phenotype. Furthermore, we uncovered a strong genetic interaction between Sox2 and Fgf20, especially in regulating the development of hair cells and supporting cells towards the basal end and the outer compartment of the organ of Corti. To explain this genetic interaction and its effects on the basal end of the organ of Corti, we provide evidence that decreased Sox2 expression delays specification, which begins at the organ of Corti apex, while Fgf20-deletion results in premature onset of differentiation, which begins near the organ of Corti base. Thereby, Sox2 and Fgf20 interact to ensure that specification occurs before differentiation towards the cochlear base. These findings reveal an intricate developmental program regulating organ of Corti development along the basal-apical axis of the cochlea.Author summaryThe mammalian cochlea contains the organ of Corti, a specialized sensory epithelium populated by hair cells and supporting cells that detect sound. Hair cells are susceptible to injury by noise, toxins, and other insults. In mammals, hair cells cannot be regenerated after injury, resulting in permanent hearing loss. Understanding genetic pathways that regulate hair cell development in the mammalian organ of Corti will help in developing methods to regenerate hair cells to treat hearing loss. Many genes are essential for hair cell and supporting cell development in the mouse organ of Corti. Among these are Sox2, Fgfr1, and Fgf20. Here, we investigate the relationship between these three genes to further define their roles in development.Interestingly, we found that Sox2 and Fgf20 interact to affect hair cell and supporting cell development in a spatially-graded manner. We found that cells toward the outer compartment and the base of the organ of Corti are more strongly affected by the loss of Sox2 and Fgf20. We provide evidence that this spatially-graded effect can be partially explained by the roles of the two genes in the precise timing of two sequential stages of organ of Corti development, specification and differentation.

The developing organ of Corti contains retinoic acid and forms supernumerary hair cells in response to exogenous retinoic acid in culture

Development ◽  
1993 ◽  
Vol 119 (4) ◽  
pp. 1041-1053 ◽  
Author(s):  
M.W. Kelley ◽  
X.M. Xu ◽  
M.A. Wagner ◽  
M.E. Warchol ◽  
J.T. Corwin
Keyword(s):  
Retinoic Acid ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Outer Hair Cells ◽  
Supporting Cells ◽  
Embryonic Mouse ◽  
Inner Hair Cells ◽  
Sensory Epithelia

The mammalian organ of Corti has one of the most highly ordered patterns of cells in any vertebrate sensory epithelium. A single row of inner hair cells and three or four rows of outer hair cells extend along its length. The factors that regulate the formation of this strict pattern are unknown. In order to determine whether retinoic acid plays a role during the development of the organ of Corti, exogenous retinoic acid was added to embryonic mouse cochleae in vitro. Exogenous retinoic acid significantly increased the number of cells that developed as hair cells and resulted in large regions of supernumerary hair cells and supporting cells containing two rows of inner hair cells and up to 11 rows of outer hair cells. The effects of retinoic acid were dependent on concentration and on the timing of its addition. Western blot analysis indicated that cellular retinoic acid binding protein (CRABP) was present in the sensory epithelium of the embryonic cochlea. The amount of CRABP apparently increased between embryonic day 14 and postnatal day 1, but CRABP was not detectable in sensory epithelia from adults. A retinoic acid reporter cell line was used to demonstrate that retinoic acid was also present in the developing organ of Corti between embryonic day 14 and postnatal day 1, and was also present in adult cochleae at least in the vicinity of the modiolus. These results suggest that retinoic acid is involved in the normal development of the organ of Corti and that the effect of retinoic acid may be to induce a population of prosensory cells to become competent to differentiate as hair cells and supporting cells.

scholarly journals Determination and Commitment of Mechanosensory Hair Cells

2002 ◽  
Vol 2 ◽  
pp. 1079-1094 ◽  
Author(s):  
Matthew W. Kelley
Keyword(s):  
Hair Cell ◽  
Signaling Pathways ◽  
Hair Cells ◽  
Progenitor Cell ◽  
Supporting Cells ◽  
Cell Identity ◽  
Final Choice ◽  
Sensory Epithelia ◽  
Cellular Factors ◽  
Mechanosensory Hair Cells

Sound and movement are perceived through the vibration of modified ciliary bundles located on the apical surfaces of specialized mechanosensory hair cells. These hair cells derive from specific regions of the otocyst that become determined to develop initially as sensory epithelia and ultimately as either hair cells or supporting cells. The number of hair cells in an individual vertebrate is surprisingly small and the ability to replace these cells varies among different classes. The molecular and cellular factors that specify hair cell identity are not known, but the results of recent experiments have begun to identify some of the signaling pathways that play important roles in hair cell development. This review will describe recent findings related to the factors that influence the final choice of a progenitor cell to develop as a hair cell and discuss their implications for the overall development of the auditory and vestibular systems.

Morphology of Synapses at the Base of Hair Cells in the Organ of Corti of the Chimpanzee

1990 ◽  
Vol 99 (3) ◽  
pp. 215-220 ◽  
Author(s):  
Joseph B. Nadol ◽  
Barbara J. Burgess
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Single Neuron ◽  
Outer Hair Cell ◽  
Mammalian Species ◽  
Organ Of Corti ◽  
Outer Hair Cells ◽  
Nerve Terminals ◽  
Section Electron ◽  
Serial Section Electron Microscopy

The synaptic morphology of inner and outer hair cells of the organ of Corti of the chimpanzee was evaluated by serial section electron microscopy. The morphology of nerve terminals and synapses at both sites was very similar to that of human and other mammalian species. Two types of nerve terminals, nonvesiculated and vesiculated, with distinct synaptic morphology were found. In addition, between some nonvesiculated endings and outer hair cells, a reciprocal synaptic relationship was seen. In such terminals there was morphologic evidence for transmission from hair cell to neuron and from neuron to hair cell between a single neuron and an outer hair cell.

Reciprocal Synapses at the Base of Outer Hair Cells in the Organ of Corti of Man

1981 ◽  
Vol 90 (1) ◽  
pp. 12-17 ◽  
Author(s):  
Joseph B. Nadol
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Outer Hair Cell ◽  
Organ Of Corti ◽  
Postsynaptic Membrane ◽  
Opposite Polarity ◽  
Outer Hair Cells ◽  
Human Organ ◽  
Single Nerve ◽  
Small Collection

Reciprocal synapses have been found between nerve terminals and the outer hair cells in the human organ of Corti. A single nerve ending of the nonvesiculated type may possess two types of synaptic specialization of opposite polarity. The first is typical of the “afferent” synapse with a presynaptic body in the hair cell and pre- and postsynaptic membrane thickening. The second consists of a small collection of presynaptic vesicles in the neural cytoplasm near the plasma membrane facing the hair cell and a subsynaptic cisterna within the hair cell cytoplasm. The second type of specialization is similar to the synapses seen in “efferent” endings. This suggests that both an afferent (hair cell to neuron) and efferent (neuron to hair cell) synaptic relationship may exist between an outer hair cell and a single nerve terminal.

scholarly journals Hair Cell Generation in Cochlear Culture Models Mediated by Novel γ-Secretase Inhibitors

2021 ◽  
Vol 9 ◽  
Author(s):  
Silvia T. Erni ◽  
John C. Gill ◽  
Carlotta Palaferri ◽  
Gabriella Fernandes ◽  
Michelle Buri ◽  
...  
Keyword(s):  
Hair Cell ◽  
Notch Signaling ◽  
Hair Cells ◽  
Round Window ◽  
Notch Pathway ◽  
Outer Hair Cells ◽  
Round Window Membrane ◽  
Sensory Cells ◽  
Supporting Cells

Sensorineural hearing loss is prevalent within society affecting the quality of life of 460 million worldwide. In the majority of cases, this is due to insult or degeneration of mechanosensory hair cells in the cochlea. In adult mammals, hair cell loss is irreversible as sensory cells are not replaced spontaneously. Genetic inhibition of Notch signaling had been shown to induce hair cell formation by transdifferentiation of supporting cells in young postnatal rodents and provided an impetus for targeting Notch pathway with small molecule inhibitors for hearing restoration. Here, the oto-regenerative potential of different γ-secretase inhibitors (GSIs) was evaluated in complementary assay models, including cell lines, organotypic cultures of the organ of Corti and cochlear organoids to characterize two novel GSIs (CPD3 and CPD8). GSI-treatment induced hair cell gene expression in all these models and was effective in increasing hair cell numbers, in particular outer hair cells, both in baseline conditions and in response to ototoxic damage. Hair cells were generated from transdifferentiation of supporting cells. Similar findings were obtained in cochlear organoid cultures, used for the first time to probe regeneration following sisomicin-induced damage. Finally, effective absorption of a novel GSI through the round window membrane and hair cell induction was attained in a whole cochlea culture model and in vivo pharmacokinetic comparisons of transtympanic delivery of GSIs and different vehicle formulations were successfully conducted in guinea pigs. This preclinical evaluation of targeting Notch signaling with novel GSIs illustrates methods of characterization for hearing restoration molecules, enabling translation to more complex animal studies and clinical research.

scholarly journals In vivo optogenetics reveals homeostatic control of cochlear sensitivity by supporting cells

2020 ◽  
Author(s):  
Victoria Lukashkina ◽  
Snezana Levic ◽  
Patricio Simões ◽  
Zhenhang Xu ◽  
Joseph DiGuiseppi ◽  
...  
Keyword(s):  
Hair Cells ◽  
Dynamic Range ◽  
Organ Of Corti ◽  
Feedback System ◽  
Supporting Cell ◽  
Outer Hair Cells ◽  
Supporting Cells ◽  
Cochlear Supporting Cells

Abstract We used optogenetics to investigate the control of auditory sensitivity by cochlear supporting cells that scaffold outer hair cells, which transduce and amplify cochlear responses to sound. In vivo and in vitro measurements of sound-induced cochlear mechanical and electrical responses were made from mice that conditionally expressed nonselective cationic channelrhodopsins in Deiters’ and outer pillar supporting cells in the organ of Corti. We demonstrated that cochlear light-stimulation and subsequent activation of channelrhodopsins depolarized the supporting cells, changed their extracellular electrical environment, and sensitized insensitive and desensitized sensitive cochlear responses to sound. We concluded that outer hair cells, Deiters’ cells and outer pillar cells interact through feedback which regulates their immediate ionic and electrical environment and controls energy flow in the mammalian cochlea to optimize its performance over its entire dynamic range. Activation of the supporting cell channelrhodopsins shunts this feedback system and restores cochlear sensitivity to a set level.

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