The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination

Development ◽  
2002 ◽  
Vol 129 (10) ◽  
pp. 2495-2505 ◽  
Author(s):  
Ping Chen ◽  
Jane E. Johnson ◽  
Huda Y. Zoghbi ◽  
Neil Segil
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Proliferating Cells ◽  
Sensory Hair ◽  
Sensory Hair Cells ◽  
Hair Cell Differentiation

During embryonic development of the inner ear, the sensory primordium that gives rise to the organ of Corti from within the cochlear epithelium is patterned into a stereotyped array of inner and outer sensory hair cells separated from each other by non-sensory supporting cells. Math1, a close homolog of the Drosophila proneural gene atonal, has been found to be both necessary and sufficient for the production of hair cells in the mouse inner ear. Our results indicate that Math1 is not required to establish the postmitotic sensory primordium from which the cells of the organ of Corti arise, but instead is limited to a role in the selection and/or differentiation of sensory hair cells from within the established primordium. This is based on the observation that Math1 is only expressed after the appearance of a zone of non-proliferating cells that delineates the sensory primordium within the cochlear anlage. The expression of Math1 is limited to a subpopulation of cells within the sensory primordium that appear to differentiate exclusively into hair cells as the sensory epithelium matures and elongates through a process that probably involves radial intercalation of cells. Furthermore, mutation of Math1 does not affect the establishment of this postmitotic sensory primordium, even though the subsequent generation of hair cells is blocked in these mutants. Finally, in Math1 mutant embryos, a subpopulation of the cells within the sensory epithelium undergo apoptosis in a temporal gradient similar to the basal-to-apical gradient of hair cell differentiation that occurs in the cochlea of wild-type animals.

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.

Hes1 is a negative regulator of inner ear hair cell differentiation

Development ◽  
2000 ◽  
Vol 127 (21) ◽  
pp. 4551-4560 ◽  
Author(s):  
J.L. Zheng ◽  
J. Shou ◽  
F. Guillemot ◽  
R. Kageyama ◽  
W.Q. Gao
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Hair Cells ◽  
Outer Hair Cells ◽  
Negative Regulator ◽  
Pcr Analysis ◽  
Loss Of Function ◽  
Hair Cell Differentiation

Hair cell fate determination in the inner ear has been shown to be controlled by specific genes. Recent loss-of-function and gain-of-function experiments have demonstrated that Math1, a mouse homolog of the Drosophila gene atonal, is essential for the production of hair cells. To identify genes that may interact with Math1 and inhibit hair cell differentiation, we have focused on Hes1, a mammalian hairy and enhancer of split homolog, which is a negative regulator of neurogenesis. We report here that targeted deletion of Hes1 leads to formation of supernumerary hair cells in the cochlea and utricle of the inner ear. RT-PCR analysis shows that Hes1 is expressed in inner ear during hair cell differentiation and its expression is maintained in adulthood. In situ hybridization with late embryonic inner ear tissue reveals that Hes1 is expressed in supporting cells, but not hair cells, of the vestibular sensory epithelium. In the cochlea, Hes1 is selectively expressed in the greater epithelial ridge and lesser epithelial ridge regions which are adjacent to inner and outer hair cells. Co-transfection experiments in postnatal rat explant cultures show that overexpression of Hes1 prevents hair cell differentiation induced by Math1. Therefore Hes1 can negatively regulate hair cell differentiation by antagonizing Math1. These results suggest that a balance between Math1 and negative regulators such as Hes1 is crucial for the production of an appropriate number of inner ear hair cells.

scholarly journals Putative pore-forming subunits of the mechano-electrical transduction channel, Tmc1/2b, require Tmie to localize to the site of mechanotransduction in zebrafish sensory hair cells

2018 ◽  
Author(s):  
Itallia V. Pacentine ◽  
Teresa Nicolson
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Transmembrane Domain ◽  
Cell Activity ◽  
Sensory Hair ◽  
Transmembrane Channel ◽  
Extracellular Region ◽  
Normal Site ◽  
Sensory Hair Cells

AbstractMutations in transmembrane inner ear (TMIE) cause deafness in humans; previous studies suggest involvement in the mechano-electrical transduction (MET) complex in sensory hair cells, but TMIE’s precise role is unclear. In tmie zebrafish mutants, we observed that GFP-tagged Tmc1 and Tmc2b, which are putative subunits of the MET channel, fail to target to the hair bundle. In contrast, overexpression of Tmie strongly enhances the targeting of Tmc2b-GFP to stereocilia. To identify the motifs of Tmie underlying the regulation of the Tmcs, we systematically deleted or replaced peptide segments. We then assessed localization and functional rescue of each mutated/chimeric form of Tmie in tmie mutants. We determined that the first putative helix was dispensable and identified a novel critical region of Tmie, the extracellular region and transmembrane domain, which mediates both mechanosensitivity and Tmc2b-GFP expression in bundles. Collectively, our results suggest that Tmie’s role in sensory hair cells is to target and stabilize Tmc subunits to the site of MET.Author summaryHair cells mediate hearing and balance through the activity of a pore-forming channel in the cell membrane. The transmembrane inner ear (TMIE) protein is an essential component of the protein complex that gates this so-called mechanotransduction channel. While it is known that loss of TMIE results in deafness, the function of TMIE within the complex is unclear. Using zebrafish as a deafness model, Pacentine and Nicolson demonstrate that Tmie is required for the localization of other essential complex members, the transmembrane channel-like (Tmc) proteins, Tmc1/2b. They then evaluate twelve unique versions of Tmie, each containing mutations to different domains of Tmie. This analysis reveals that some mutations in Tmie cause dysfunctional gating of the channel as demonstrated through reduced hair cell activity, and that these same dysfunctional versions also display reduced Tmc expression at the normal site of the channel. These findings link hair cell activity with the levels of Tmc in the bundle, reinforcing the currently-debated notion that the Tmcs are the pore-forming subunits of the mechanotransduction channel. The authors conclude that Tmie, through distinct regions, is involved in both trafficking and stabilizing the Tmcs at the site of mechanotransduction.

Notch signaling regulates the pattern of auditory hair cell differentiation in mammals

Development ◽  
2000 ◽  
Vol 127 (15) ◽  
pp. 3373-3383 ◽  
Author(s):  
A. Zine ◽  
T.R. Van De Water ◽  
F. de Ribaupierre
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Notch Signaling ◽  
Cell Fate ◽  
Hair Cells ◽  
Expression Patterns ◽  
Sensory Epithelium ◽  
Supporting Cells ◽  
Hair Cell Differentiation ◽  
Notch1 Signaling Pathway

The development of the mammalian cochlea is an example of patterning in the peripheral nervous system. Sensory hair cells and supporting cells in the cochlea differentiate via regional and cell fate specification. The Notch signaling components shows both distinct and overlapping expression patterns of Notch1 receptor and its ligands Jagged1 (Jag1) and Jagged2 (Jag2) in the developing auditory epithelium of the rat. On embryonic day 16 (E16), many precursor cells within the Kolliker's organ immunostained for the presence of both Notch1 and Jag1, while the area of hair cell precursors did not express either Notch1 and Jag1. During initial events of hair cell differentiation between E18 and birth, Notch1 and Jag1 expression predominated in supporting cells and Jag2 in nascent hair cells. Early after birth, Jag2 expression decreased in hair cells while the pattern of Notch1 expression now included both supporting cells and hair cells. We show that the normal pattern of hair cell differentiation is disrupted by alteration of Notch signaling. A decrease of either Notch1 or Jag1 expression by antisense oligonucleotides in cultures of the developing sensory epithelium resulted in an increase in the number of hair cells. Our data suggest that the Notch1 signaling pathway is involved in a complex interplay between the consequences of different ligand-Notch1 combinations during cochlear morphogenesis and the phases of hair cell differentiation.

scholarly journals Identification of a 275-kD protein associated with the apical surfaces of sensory hair cells in the avian inner ear.

1990 ◽  
Vol 110 (4) ◽  
pp. 1055-1066 ◽  
Author(s):  
G P Richardson ◽  
S Bartolami ◽  
I J Russell
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Proximal Region ◽  
Basilar Papilla ◽  
Relative Molecular Mass ◽  
Apical Surface ◽  
Sensory Hair ◽  
Sensory Hair Cells ◽  
Avian Inner Ear

Immunological techniques have been used to generate both polyclonal and monoclonal antibodies specific for the apical ends of sensory hair cells in the avian inner ear. The hair cell antigen recognized by these antibodies is soluble in nonionic detergent, behaves on sucrose gradients primarily as a 16S particle, and, after immunoprecipitation, migrates as a polypeptide with a relative molecular mass of 275 kD on 5% SDS gels under reducing conditions. The antigen can be detected with scanning immunoelectron microscopy on the apical surface of the cell and on the stereocilia bundle but not on the kinocilium. Double label studies indicate that the entire stereocilia bundle is stained in the lagena macula (a vestibular organ), whereas in the basilar papilla (an auditory organ) only the proximal region of the stereocilia bundle nearest to the apical surface is stained. The monoclonal anti-hair cell antibodies do not stain brain, tongue, lung, liver, heart, crop, gizzard, small intestine, skeletal muscle, feather, skin, or eye tissues but do specifically stain renal corpuscles in the kidney. Experiments using organotypic cultures of the embryonic lagena macula indicate that the antibodies cause a significant increase in the steady-state stiffness of the stereocilia bundle but do not inhibit mechanotransduction. The antibodies should provide a suitable marker and/or tool for the purification of the apical sensory membrane of the hair cell.

scholarly journals The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1

Development ◽  
1999 ◽  
Vol 126 (24) ◽  
pp. 5669-5678 ◽  
Author(s):  
B.B. Riley ◽  
M. Chiang ◽  
L. Farmer ◽  
R. Heck
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Lateral Inhibition ◽  
Hair Cells ◽  
Fold Increase ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Hair Cell Differentiation

Recent studies of inner ear development suggest that hair cells and support cells arise within a common equivalence group by cell-cell interactions mediated by Delta and Notch proteins. We have extended these studies by analyzing the effects of a mutant allele of the zebrafish deltaA gene, deltaA(dx2), which encodes a dominant-negative protein. deltaA(dx2/dx2)homozygous mutants develop with a 5- to 6-fold excess of hair cells and a severe deficiency of support cells. In addition, deltaA(dx2/dx2) mutants show an increased number of cells expressing pax2.1 in regions where hair cells are normally produced. Immunohistological analysis of wild-type and deltaA(dx2/dx2) mutant embryos confirmed that pax2.1 is expressed during the initial stages of hair cell differentiation and is later maintained at high levels in mature hair cells. In contrast, pax2.1 is not expressed in support cells. To address the function of pax2.1, we analyzed hair cell differentiation in no isthmus mutant embryos, which are deficient for pax2.1 function. no isthmus mutant embryos develop with approximately twice the normal number of hair cells. This neurogenic defect correlates with reduced levels of expression of deltaA and deltaD in the hair cells in no isthmus mutants. Analysis of deltaA(dx2/dx2); no isthmus double mutants showed that no isthmus suppresses the deltaA(dx2) phenotype, probably by reducing levels of the dominant-negative mutant protein. This interpretation was supported by analysis of T(msxB)(b220), a deletion that removes the deltaA locus. Reducing the dose of deltaA(dx2) by generating deltaA(dx2)/T(msxB)(b220)trans-heterozygotes weakens the neurogenic effects of deltaA(dx2), whereas T(msxB)(b220) enhances the neurogenic defects of no isthmus. mind bomb, another strong neurogenic mutation that may disrupt reception of Delta signals, causes a 10-fold increase in hair cell production and is epistatic to both no isthmus and deltaA(dx2). These data indicate that deltaA expressed by hair cells normally prevents adjacent cells from adopting the same cell fate, and that pax2.1 is required for normal levels of Delta-mediated lateral inhibition.

scholarly journals Hair necessities: Hair cell differentiation and regeneration

2002 ◽  
Vol 24 (6) ◽  
pp. 9-11
Author(s):  
Matthew Holley
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Structural Diversity ◽  
Sensory Epithelium ◽  
Animal Kingdom ◽  
Hair Cell Differentiation ◽  
Human Hearing ◽  
Mechanosensory Hair Cells

Human hearing is governed by approximately 15 500 mechanosensory hair cells in each ear. These cells are located within the organ of Corti, the elongated auditory sensory epithelium that is stretched inside the coiled cochleae of the inner ear. Despite the structural diversity between the organs of hearing throughout the animal kingdom, hair cells are instantly recognizable. Their shapes and sizes vary considerably, but their apices carry a characteristic bundle of actin-filled stereocilia, or hairs, whose tips are connected by stretch-sensitive ‘tip-links’1. However, unlike most other animals, mammals do not regenerate lost hair cells2, consequently most forms of deafness are irreversible.

scholarly journals A counter gradient of Activin A and follistatin instructs the timing of hair cell differentiation in the murine cochlea

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Meenakshi Prajapati-DiNubila ◽  
Ana Benito-Gonzalez ◽  
Erin Jennifer Golden ◽  
Shuran Zhang ◽  
Angelika Doetzlhofer
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Hair Cells ◽  
Activin A ◽  
Sensory Epithelium ◽  
Outer Hair Cells ◽  
Longitudinal Gradient ◽  
Hair Cell Differentiation ◽  
Local Gradient ◽  
Molecular Signals

The mammalian auditory sensory epithelium has one of the most stereotyped cellular patterns known in vertebrates. Mechano-sensory hair cells are arranged in precise rows, with one row of inner and three rows of outer hair cells spanning the length of the spiral-shaped sensory epithelium. Aiding such precise cellular patterning, differentiation of the auditory sensory epithelium is precisely timed and follows a steep longitudinal gradient. The molecular signals that promote auditory sensory differentiation and instruct its graded pattern are largely unknown. Here, we identify Activin A and its antagonist follistatin as key regulators of hair cell differentiation and show, using mouse genetic approaches, that a local gradient of Activin A signaling within the auditory sensory epithelium times the longitudinal gradient of hair cell differentiation. Furthermore, we provide evidence that Activin-type signaling regulates a radial gradient of terminal mitosis within the auditory sensory epithelium, which constitutes a novel mechanism for limiting the number of inner hair cells being produced.

scholarly journals Early appearance of key transcription factors influence the spatiotemporal development of the human inner ear

2019 ◽  
Vol 379 (3) ◽  
pp. 459-471 ◽  
Author(s):  
Lejo Johnson Chacko ◽  
Consolato Sergi ◽  
Theresa Eberharter ◽  
Jozsef Dudas ◽  
Helge Rask-Andersen ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Inner Ear ◽  
Hair Cells ◽  
Transforming Growth Factor ◽  
Expression Patterns ◽  
Organ Of Corti ◽  
Sensory Epithelium ◽  
Receptor Expression ◽  
Cell Phenotype ◽  
Type I

AbstractExpression patterns of transcription factors leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), transforming growth factor-β-activated kinase-1 (TAK1), SRY (sex-determining region Y)-box 2 (SOX2), and GATA binding protein 3 (GATA3) in the developing human fetal inner ear were studied between the gestation weeks 9 and 12. Further development of cochlear apex between gestational weeks 11 and 16 (GW11 and GW16) was examined using transmission electron microscopy. LGR5 was evident in the apical poles of the sensory epithelium of the cochlear duct and the vestibular end organs at GW11. Immunostaining was limited to hair cells of the organ of Corti by GW12. TAK1 was immune positive in inner hair cells of the organ of Corti by GW12 and colocalized with p75 neurotrophic receptor expression. Expression for SOX2 was confined primarily to the supporting cells of utricle at the earliest stage examined at GW9. Intense expression for GATA3 was presented in the cochlear sensory epithelium and spiral ganglia at GW9. Expression of GATA3 was present along the midline of both the utricle and saccule in the zone corresponding to the striolar reversal zone where the hair cell phenotype switches from type I to type II. The spatiotemporal gradient of the development of the organ of Corti was also evident with the apex of the cochlea forming by GW16. It seems that highly specific staining patterns of several transcriptions factors are critical in guiding the genesis of the inner ear over development. Our findings suggest that the spatiotemporal gradient in cochlear development extends at least until gestational week 16.

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