scholarly journals Shear forces drive precise patterning of hair cells in the mammalian inner ear

2019 ◽  
Author(s):  
Roie Cohen ◽  
Liat Amir-Zilberstein ◽  
Micha Hersch ◽  
Shiran Woland ◽  
Shahar Taiber ◽  
...  
Keyword(s):  
Hair Cells ◽  
Organ Of Corti ◽  
Time Lapse ◽  
Supporting Cells ◽  
Cellular Junctions ◽  
Shear Motion ◽  
Time Lapse Imaging ◽  
Global And Local ◽  
Induced Crystallization ◽  
Quantitative Morphological Analysis

AbstractPrecise cellular organizations are required for the function of many organs and tissues. It is often unclear, however, how such precise patterns emerge during development. The mammalian hearing organ, the organ of Corti, consists of a remarkably organized pattern of four rows of hair cells (HCs) interspersed by non-sensory supporting cells (SCs). This checkerboard-like pattern of HCs and SCs emerges from a disordered epithelium over several days, yet the transition to an ordered cellular pattern is not well understood. Using a combination of quantitative morphological analysis and time-lapse imaging of mouse cochlear explants, we show here that patterning of the organ of Corti involves dynamic reorganizations that include lateral shear motion, cell intercalations, and delaminations. A mathematical model, where tissue morphology is described in terms of the mechanical forces that act on cells and cellular junctions, suggests that global shear on HCs and local repulsion between HCs are sufficient to drive the tissue into the final checkerboard-like pattern. Our findings suggest that precise patterns can emerge during development from reorganization processes, driven by a combination of global and local forces in a process analogous to shear-induced crystallization.

scholarly journals Mechanical forces drive ordered patterning of hair cells in the mammalian inner ear

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Roie Cohen ◽  
Liat Amir-Zilberstein ◽  
Micha Hersch ◽  
Shiran Woland ◽  
Olga Loza ◽  
...  
Keyword(s):  
Hair Cells ◽  
Organ Of Corti ◽  
Time Lapse ◽  
Mechanical Forces ◽  
Intercellular Signaling ◽  
Periodic Patterns ◽  
Mechanical Models ◽  
Granular Physics ◽  
Shear Motion ◽  
Time Lapse Imaging

Abstract Periodic organization of cells is required for the function of many organs and tissues. The development of such periodic patterns is typically associated with mechanisms based on intercellular signaling such as lateral inhibition and Turing patterning. Here we show that the transition from disordered to ordered checkerboard-like pattern of hair cells and supporting cells in the mammalian hearing organ, the organ of Corti, is likely based on mechanical forces rather than signaling events. Using time-lapse imaging of mouse cochlear explants, we show that hair cells rearrange gradually into a checkerboard-like pattern through a tissue-wide shear motion that coordinates intercalation and delamination events. Using mechanical models of the tissue, we show that global shear and local repulsion forces on hair cells are sufficient to drive the transition from disordered to ordered cellular pattern. Our findings suggest that mechanical forces drive ordered hair cell patterning in a process strikingly analogous to the process of shear-induced crystallization in polymer and granular physics.

p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti

Development ◽  
1999 ◽  
Vol 126 (8) ◽  
pp. 1581-1590 ◽  
Author(s):  
P. Chen ◽  
N. Segil
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Inner Ear ◽  
Hair Cells ◽  
Cellular Proliferation ◽  
Adult Life ◽  
Organ Of Corti ◽  
Morphological Development ◽  
Supporting Cells ◽  
P27 Kip1

Strict control of cellular proliferation is required to shape the complex structures of the developing embryo. The organ of Corti, the auditory neuroepithelium of the inner ear in mammals, consists of two types of terminally differentiated mechanosensory hair cells and at least four types of supporting cells arrayed precisely along the length of the spiral cochlea. In mice, the progenitors of greater than 80% of both hair cells and supporting cells undergo their terminal division between embryonic day 13 (E13) and E14. As in humans, these cells persist in a non-proliferative state throughout the adult life of the animal. Here we report that the correct timing of cell cycle withdrawal in the developing organ of Corti requires p27(Kip1), a cyclin-dependent kinase inhibitor that functions as an inhibitor of cell cycle progression. p27(Kip1) expression is induced in the primordial organ of Corti between E12 and E14, correlating with the cessation of cell division of the progenitors of the hair cells and supporting cells. In wild-type animals, p27(Kip1) expression is downregulated during subsequent hair cell differentiation, but it persists at high levels in differentiated supporting cells of the mature organ of Corti. In mice with a targeted deletion of the p27(Kip1) gene, proliferation of the sensory cell progenitors continues after E14, leading to the appearance of supernumerary hair cells and supporting cells. In the absence of p27(Kip1), mitotically active cells are still observed in the organ of Corti of postnatal day 6 animals, suggesting that the persistence of p27(Kip1) expression in mature supporting cells may contribute to the maintenance of quiescence in this tissue and, possibly, to its inability to regenerate. Homozygous mutant mice are severely hearing impaired. Thus, p27(Kip1) provides a link between developmental control of cell proliferation and the morphological development of the inner ear.

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.

scholarly journals HES-1 and COUP-TFI shRNA Knocking Down Give Rises to New Hair Cells and Supporting Cells in Organ of Corti Organotypic Culture

2014 ◽  
Vol 18 (S 01) ◽  
Author(s):  
Jeanne Ferraz ◽  
Ana Batissoco ◽  
Bryan Strauss ◽  
Daniela Zanatta ◽  
Karina Lezirovitz ◽  
...  
Keyword(s):  
Hair Cells ◽  
Organotypic Culture ◽  
Organ Of Corti ◽  
Supporting Cells

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.

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