scholarly journals GFI1 functions to repress neuronal gene expression in the developing inner ear hair cells

Development ◽  
2020 ◽  
Vol 147 (17) ◽  
pp. dev186015 ◽  
Author(s):  
Maggie S. Matern ◽  
Beatrice Milon ◽  
Erika L. Lipford ◽  
Mark McMurray ◽  
Yoko Ogawa ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Neuronal Development ◽  
Cell Development ◽  
Vestibular Hair Cells ◽  
Normal Functional ◽  
Neuronal Genes ◽  
Hair Cell Differentiation

ABSTRACTDespite the known importance of the transcription factors ATOH1, POU4F3 and GFI1 in hair cell development and regeneration, their downstream transcriptional cascades in the inner ear remain largely unknown. Here, we have used Gfi1cre;RiboTag mice to evaluate changes to the hair cell translatome in the absence of GFI1. We identify a systematic downregulation of hair cell differentiation genes, concomitant with robust upregulation of neuronal genes in the GFI1-deficient hair cells. This includes increased expression of neuronal-associated transcription factors (e.g. Pou4f1) as well as transcription factors that serve dual roles in hair cell and neuronal development (e.g. Neurod1, Atoh1 and Insm1). We further show that the upregulated genes are consistent with the NEUROD1 regulon and are normally expressed in hair cells prior to GFI1 onset. Additionally, minimal overlap of differentially expressed genes in auditory and vestibular hair cells suggests that GFI1 serves different roles in these systems. From these data, we propose a dual mechanism for GFI1 in promoting hair cell development, consisting of repression of neuronal-associated genes as well as activation of hair cell-specific genes required for normal functional maturation.

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 A Critical E-box in Barhl1 3′ Enhancer Is Essential for Auditory Hair Cell Differentiation

Cells ◽  
2019 ◽  
Vol 8 (5) ◽  
pp. 458 ◽  
Author(s):  
Kun Hou ◽  
Hui Jiang ◽  
Md. Rezaul Karim ◽  
Chao Zhong ◽  
Zhouwen Xu ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
Hair Cell ◽  
Hair Cells ◽  
Embryonic Stem ◽  
Cell Development ◽  
Homologous Gene ◽  
Auditory Hair Cells ◽  
E Box ◽  
Hair Cell Differentiation

Barhl1, a mouse homologous gene of Drosophila BarH class homeobox genes, is highly expressed within the inner ear and crucial for the long-term maintenance of auditory hair cells that mediate hearing and balance, yet little is known about the molecular events underlying Barhl1 regulation and function in hair cells. In this study, through data mining and in vitro report assay, we firstly identified Barhl1 as a direct target gene of Atoh1 and one E-box (E3) in Barhl1 3’ enhancer is crucial for Atoh1-mediated Barhl1 activation. Then we generated a mouse embryonic stem cell (mESC) line carrying disruptions on this E3 site E-box (CAGCTG) using CRISPR/Cas9 technology and this E3 mutated mESC line is further subjected to an efficient stepwise hair cell differentiation strategy in vitro. Disruptions on this E3 site caused dramatic loss of Barhl1 expression and significantly reduced the number of induced hair cell-like cells, while no affections on the differentiation toward early primitive ectoderm-like cells and otic progenitors. Finally, through RNA-seq profiling and gene ontology (GO) enrichment analysis, we found that this E3 box was indispensable for Barhl1 expression to maintain hair cell development and normal functions. We also compared the transcriptional profiles of induced cells from CDS mutated and E3 mutated mESCs, respectively, and got very consistent results except the Barhl1 transcript itself. These observations indicated that Atoh1-mediated Barhl1 expression could have important roles during auditory hair cell development. In brief, our findings delineate the detail molecular mechanism of Barhl1 expression regulation in auditory hair cell differentiation.

scholarly journals The cell biology of hearing

2010 ◽  
Vol 190 (1) ◽  
pp. 9-20 ◽  
Author(s):  
Martin Schwander ◽  
Bechara Kachar ◽  
Ulrich Müller
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Cell Biology ◽  
Cell Development ◽  
Biological Mechanisms ◽  
Electrical Signals ◽  
Mechanosensory Hair Cells

Mammals have an astonishing ability to sense and discriminate sounds of different frequencies and intensities. Fundamental for this process are mechanosensory hair cells in the inner ear that convert sound-induced vibrations into electrical signals. The study of genes that are linked to deafness has provided insights into the cell biological mechanisms that control hair cell development and their function as mechanosensors.

Hair cell development in vivo and in vitro: Analysis by using a monoclonal antibody specific to hair cells in the chick inner ear

2002 ◽  
Vol 445 (2) ◽  
pp. 176-198
Author(s):  
Kenji Kondo ◽  
Hiroshi Sagara ◽  
Kazushige Hirosawa ◽  
Kimitaka Kaga ◽  
Satsuki Matsushima ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Cell Development ◽  
Vitro Analysis ◽  
In Vitro Analysis

scholarly journals Conserved and Divergent Principles of Planar Polarity Revealed by Hair Cell Development and Function

2021 ◽  
Vol 15 ◽  
Author(s):  
Michael R. Deans
Keyword(s):  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Model Organism ◽  
Vestibular Function ◽  
Sensory Receptor ◽  
Apical Surface ◽  
Planar Polarity ◽  
Vestibular Hair Cells ◽  
Sensory Epithelia

Planar polarity describes the organization and orientation of polarized cells or cellular structures within the plane of an epithelium. The sensory receptor hair cells of the vertebrate inner ear have been recognized as a preeminent vertebrate model system for studying planar polarity and its development. This is principally because planar polarity in the inner ear is structurally and molecularly apparent and therefore easy to visualize. Inner ear planar polarity is also functionally significant because hair cells are mechanosensors stimulated by sound or motion and planar polarity underlies the mechanosensory mechanism, thereby facilitating the auditory and vestibular functions of the ear. Structurally, hair cell planar polarity is evident in the organization of a polarized bundle of actin-based protrusions from the apical surface called stereocilia that is necessary for mechanosensation and when stereociliary bundle is disrupted auditory and vestibular behavioral deficits emerge. Hair cells are distributed between six sensory epithelia within the inner ear that have evolved unique patterns of planar polarity that facilitate auditory or vestibular function. Thus, specialized adaptations of planar polarity have occurred that distinguish auditory and vestibular hair cells and will be described throughout this review. There are also three levels of planar polarity organization that can be visualized within the vertebrate inner ear. These are the intrinsic polarity of individual hair cells, the planar cell polarity or coordinated orientation of cells within the epithelia, and planar bipolarity; an organization unique to a subset of vestibular hair cells in which the stereociliary bundles are oriented in opposite directions but remain aligned along a common polarity axis. The inner ear with its complement of auditory and vestibular sensory epithelia allows these levels, and the inter-relationships between them, to be studied using a single model organism. The purpose of this review is to introduce the functional significance of planar polarity in the auditory and vestibular systems and our contemporary understanding of the developmental mechanisms associated with organizing planar polarity at these three cellular levels.

scholarly journals Transcription Factor Reprogramming in the Inner Ear: Turning on Cell Fate Switches to Regenerate Sensory Hair Cells

2021 ◽  
Vol 15 ◽  
Author(s):  
Amrita A. Iyer ◽  
Andrew K. Groves
Keyword(s):  
Transcription Factor ◽  
Transcription Factors ◽  
Hair Cell ◽  
Inner Ear ◽  
Cell Fate ◽  
Hair Cells ◽  
Cell Regeneration ◽  
Cell Type ◽  
Hair Cell Regeneration ◽  
Supporting Cells

Non-mammalian vertebrates can restore their auditory and vestibular hair cells naturally by triggering the regeneration of adjacent supporting cells. The transcription factor ATOH1 is a key regulator of hair cell development and regeneration in the inner ear. Following the death of hair cells, supporting cells upregulate ATOH1 and give rise to new hair cells. However, in the mature mammalian cochlea, such natural regeneration of hair cells is largely absent. Transcription factor reprogramming has been used in many tissues to convert one cell type into another, with the long-term hope of achieving tissue regeneration. Reprogramming transcription factors work by altering the transcriptomic and epigenetic landscapes in a target cell, resulting in a fate change to the desired cell type. Several studies have shown that ATOH1 is capable of reprogramming cochlear non-sensory tissue into cells resembling hair cells in young animals. However, the reprogramming ability of ATOH1 is lost with age, implying that the potency of individual hair cell-specific transcription factors may be reduced or lost over time by mechanisms that are still not clear. To circumvent this, combinations of key hair cell transcription factors have been used to promote hair cell regeneration in older animals. In this review, we summarize recent findings that have identified and studied these reprogramming factor combinations for hair cell regeneration. Finally, we discuss the important questions that emerge from these findings, particularly the feasibility of therapeutic strategies using reprogramming factors to restore human hearing in the future.

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.

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.

scholarly journals SoxC transcription factors are essential for the development of the inner ear

2015 ◽  
Vol 112 (45) ◽  
pp. 14066-14071 ◽  
Author(s):  
Ksenia Gnedeva ◽  
A. J. Hudspeth
Keyword(s):  
Transcription Factors ◽  
Hair Cell ◽  
Inner Ear ◽  
Hair Cells ◽  
Supporting Cell ◽  
Sensory Epithelia ◽  
Enhanced Expression ◽  
Mechanosensory Receptors

Hair cells, the mechanosensory receptors of the inner ear, underlie the senses of hearing and balance. Adult mammals cannot adequately replenish lost hair cells, whose loss often results in deafness or balance disorders. To determine the molecular basis of this deficiency, we investigated the development of a murine vestibular organ, the utricle. Here we show that two members of the SoxC family of transcription factors, Sox4 and Sox11, are down-regulated after the epoch of hair cell development. Conditional ablation of SoxC genes in vivo results in stunted sensory organs of the inner ear and loss of hair cells. Enhanced expression of SoxC genes in vitro conversely restores supporting cell proliferation and the production of new hair cells in adult sensory epithelia. These results imply that SoxC genes govern hair cell production and thus advance these genes as targets for the restoration of hearing and balance.

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