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.

scholarly journals LIN28B/let-7control the ability of neonatal murine auditory supporting cells to generate hair cells through mTOR signaling

2020 ◽  
Vol 117 (36) ◽  
pp. 22225-22236
Author(s):  
Xiao-Jun Li ◽  
Angelika Doetzlhofer
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Rna Binding ◽  
Mammalian Target Of Rapamycin ◽  
Cell Loss ◽  
Supporting Cell ◽  
Dependent Manner ◽  
Cell Plasticity ◽  
Supporting Cells ◽  
Cochlear Hair Cells

Mechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mammalian target of rapamycin (mTOR) activity. Employing murine cochlear organoid and explant cultures to model mitotic and nonmitotic mechanisms of hair cell generation, we show that loss of LIN28B function, due to its conditional deletion, or due to overexpression of the antagonistic miRNAlet-7g, suppressed Akt-mTOR complex 1 (mTORC1) activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and nonmitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.

scholarly journals Loss of Fgfr3 leads to excess hair cell development in the mouse organ of Corti

2007 ◽  
Vol 236 (2) ◽  
pp. 525-533 ◽  
Author(s):  
Toshinori Hayashi ◽  
Dale Cunningham ◽  
Olivia Bermingham-McDonogh
Keyword(s):  
Hair Cell ◽  
Organ Of Corti ◽  
Cell Development ◽  
Mouse Organ

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 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.

scholarly journals Deletion of Clusterin Protects Cochlear Hair Cells against Hair Cell Aging and Ototoxicity

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Xiaochang Zhao ◽  
Heidi J. Henderson ◽  
Tianying Wang ◽  
Bo Liu ◽  
Yi Li
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Sensorineural Hearing ◽  
Cell Aging ◽  
Supporting Cells ◽  
Drug Induced ◽  
Cochlear Hair Cells ◽  
Age Related

Hearing loss is a debilitating disease that affects 10% of adults worldwide. Most sensorineural hearing loss is caused by the loss of mechanosensitive hair cells in the cochlea, often due to aging, noise, and ototoxic drugs. The identification of genes that can be targeted to slow aging and reduce the vulnerability of hair cells to insults is critical for the prevention of sensorineural hearing loss. Our previous cell-specific transcriptome analysis of adult cochlear hair cells and supporting cells showed that Clu, encoding a secreted chaperone that is involved in several basic biological events, such as cell death, tumor progression, and neurodegenerative disorders, is expressed in hair cells and supporting cells. We generated Clu-null mice (C57BL/6) to investigate its role in the organ of Corti, the sensory epithelium responsible for hearing in the mammalian cochlea. We showed that the deletion of Clu did not affect the development of hair cells and supporting cells; hair cells and supporting cells appeared normal at 1 month of age. Auditory function tests showed that Clu-null mice had hearing thresholds comparable to those of wild-type littermates before 3 months of age. Interestingly, Clu-null mice displayed less hair cell and hearing loss compared to their wildtype littermates after 3 months. Furthermore, the deletion of Clu is protected against aminoglycoside-induced hair cell loss in both in vivo and in vitro models. Our findings suggested that the inhibition of Clu expression could represent a potential therapeutic strategy for the alleviation of age-related and ototoxic drug-induced hearing loss.

scholarly journals LIN28B controls the regenerative capacity of neonatal murine auditory supporting cells through activation of mTOR signaling

2020 ◽  
Author(s):  
Xiaojun Li ◽  
Angelika Doetzlhofer
Keyword(s):  
Hair Cell ◽  
Hair Cells ◽  
Rna Binding ◽  
Cell Loss ◽  
Supporting Cell ◽  
Mtor Signaling ◽  
Cell Plasticity ◽  
Supporting Cells ◽  
Regenerative Capacity ◽  
Mtor Activity

ABSTRACTMechano-sensory hair cells within the inner ear cochlea are essential for the detection of sound. In mammals, cochlear hair cells are only produced during development and their loss, due to disease or trauma, is a leading cause of deafness. In the immature cochlea, prior to the onset of hearing, hair cell loss stimulates neighboring supporting cells to act as hair cell progenitors and produce new hair cells. However, for reasons unknown, such regenerative capacity (plasticity) is lost once supporting cells undergo maturation. Here, we demonstrate that the RNA binding protein LIN28B plays an important role in the production of hair cells by supporting cells and provide evidence that the developmental drop in supporting cell plasticity in the mammalian cochlea is, at least in part, a product of declining LIN28B-mTOR activity. Employing murine cochlear organoid and explant cultures to model mitotic and non-mitotic mechanisms of hair cell generation, we show that loss of Lin28b function, due to its conditional deletion, or due to overexpression of the antagonistic miRNA let-7g, suppressed Akt-mTORC1 activity and renders young, immature supporting cells incapable of generating hair cells. Conversely, we found that LIN28B overexpression increased Akt-mTORC1 activity and allowed supporting cells that were undergoing maturation to de-differentiate into progenitor-like cells and to produce hair cells via mitotic and non-mitotic mechanisms. Finally, using the mTORC1 inhibitor rapamycin, we demonstrate that LIN28B promotes supporting cell plasticity in an mTORC1-dependent manner.SIGNIFICANCE STATEMENTCochlear hair cell loss is a leading cause of deafness in humans and other mammals. In the immature cochlea lost hair cells are regenerated by neighboring glia-like supporting cells. However, for reasons unknown, such regenerative capacity is rapidly lost as supporting cells undergo maturation. Here we identify a direct link between LIN28B-mTOR activity and supporting cell plasticity. Mimicking later developmental stages, we found that loss of the RNA binding protein LIN28B attenuated mTOR signaling and rendered young, immature supporting cells incapable of producing hair cells. Conversely, we found that re-expression of LIN28B reinstated the ability of maturing supporting cells to revert to a progenitor-like state and generate hair cells via activation of mTOR signaling.

scholarly journals Essential Role of Sptan1 in Cochlear Hair Cell Morphology and Function Via Focal Adhesion Signaling

2021 ◽  
Author(s):  
Qingxiu Yao ◽  
Hui Wang ◽  
Hengchao Chen ◽  
Zhuangzhuang Li ◽  
Yumeng Jiang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Focal Adhesion ◽  
Hair Cells ◽  
Focal Adhesions ◽  
Organ Of Corti ◽  
Cochlear Hair Cell ◽  
Cuticular Plate ◽  
And Function

AbstractHearing loss is the most common human sensory deficit. Hearing relies on stereocilia, inserted into the cuticular plate of hair cells (HCs), where they play an important role in the perception of sound and its transmission. Although numerous genes have been associated with hearing loss, the function of many hair cell genes has yet to be elucidated. Herein, we focused on nonerythroid spectrin αII (SPTAN1), abundant in the cuticular plate, surrounding the rootlets of stereocilia and along the plasma membrane. Interestingly, mice with HC-specific Sptan1 knockout exhibited rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of HCs from middle and apical turns of the cochlea during early postnatal stages. Additionally, Sptan1 deficiency led to the decreased spreading of House Ear Institute-Organ of Corti 1 cells, and induced abnormal formation of focal adhesions and integrin signaling in mouse HCs. Altogether, our findings highlight SPTAN1 as a critical molecule for HC stereocilia morphology and auditory function via regulation of focal adhesion signaling.

Hearing loss caused by progressive degeneration of cochlear hair cells in mice deficient for the Barhl1 homeobox gene

Development ◽  
2002 ◽  
Vol 129 (14) ◽  
pp. 3523-3532 ◽  
Author(s):  
Shengguo Li ◽  
Sandy M. Price ◽  
Hugh Cahill ◽  
David K. Ryugo ◽  
Michael M. Shen ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Cochlear Hair Cells ◽  
Sensory Hair ◽  
Progressive Degeneration ◽  
Age Related ◽  
Sensory Hair Cells

The cochlea of the mammalian inner ear contains three rows of outer hair cells and a single row of inner hair cells. These hair cell receptors reside in the organ of Corti and function to transduce mechanical stimuli into electrical signals that mediate hearing. To date, the molecular mechanisms underlying the maintenance of these delicate sensory hair cells are unknown. We report that targeted disruption of Barhl1, a mouse homolog of the Drosophila BarH homeobox genes, results in severe to profound hearing loss, providing a unique model for the study of age-related human deafness disorders. Barhl1 is expressed in all sensory hair cells during inner ear development, 2 days after the onset of hair cell generation. Loss of Barhl1 function in mice results in age-related progressive degeneration of both outer and inner hair cells in the organ of Corti, following two reciprocal longitudinal gradients. Our data together indicate an essential role for Barhl1 in the long-term maintenance of cochlear hair cells, but not in the determination or differentiation of these cells.

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

PLoS Genetics ◽  
2019 ◽  
Vol 15 (7) ◽  
pp. e1008254 ◽  
Author(s):  
Lu M. Yang ◽  
Kathryn S. E. Cheah ◽  
Sung-Ho Huh ◽  
David M. Ornitz
Keyword(s):  
Hair Cell ◽  
Organ Of Corti ◽  
Supporting Cell ◽  
Cell Development

Intracellular recordings from supporting cells in the guinea pig cochlea: DC potentials

1990 ◽  
Vol 64 (2) ◽  
pp. 617-636 ◽  
Author(s):  
E. C. Oesterle ◽  
P. Dallos
Keyword(s):  
Guinea Pig ◽  
Hair Cell ◽  
Hair Cells ◽  
Extracellular Fluid ◽  
Organ Of Corti ◽  
Supporting Cells ◽  
Adjacent Organ ◽  
Cell Responses ◽  
Support Cell ◽  
Guinea Pig Cochlea

1. Supporting cells and hair cells from the low-frequency region of the guinea pig cochlea were studied in vivo using intracellular recording and horseradish-peroxidase (HRP) marking techniques. 2. The response of third- and fourth-turn support cells to tone bursts is composed of a number of components: an AC component at the frequency of the stimulating tone, harmonic components, a DC component present at the onset of the stimulating tone (the early DC), a slowly developing depolarization, and a slowly decaying afterpotential. 3. The early DC of support-cell responses is generally less than or equal to that in the adjacent organ of Corti fluids [at the best frequency (BF) for an 80 or 90 dB sound pressure level (SPL) stimulus the average early DC of support-cell responses is 0.9 times that of the adjacent fluids; n = 71], and both are less than that seen in the hair cells [average early DC of inner hair-cell (IHC) responses at the same sound levels is 14.2 times that in the adjacent organ fluids, n = 15; average early DC of outer hair-cell (OHC) responses is 11.5 times that in nearby organ fluids, n = 2)]. 4. The end DC, magnitude of the DC response shortly before signal end, in responses of support cells deep into Corti's organ [e.g., pillar, inner phalangeal, border cells] is often greater than that recorded in the potentials of the adjacent organ fluids (e.g., for an 80 or 90 dB SPL stimulus at the BF with a 30 ms steady-state time, the average end DC of the support cells deep into the organ is 2 times that of the adjacent organ fluids, n = 42). In contrast, the end DC for the responses of peripheral support cells--the Hensen's cells--generally equals, or is smaller than, the extracellular-fluid counterpart (for an 80 or 90 dB SPL stimulus, the average end DC of Hensen's cells is 0.9 times that of the nearby, outer-tunnel fluids, n = 29). Thus a difference exists across support-cell type with respect to support-cell end DC vis-a-vis that of the adjacent organ of Corti fluids. 5. A slowly increasing depolarization is often present in moderate and high-level support-cell responses. It is not normally present in IHC or OHC responses. Magnitude of the slowly increasing depolarization, the slow DC, is dependent on stimulus duration and stimulus level.(ABSTRACT TRUNCATED AT 400 WORDS)

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