Neurog1 can partially substitute for Atoh1 function in hair cell differentiation and maintenance during organ of Corti development

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.

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Faculty Opinions recommendation of Hedgehog signaling regulates prosensory cell properties during the basal-to-apical wave of hair cell differentiation in the mammalian cochlea.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718075777.793482639 ◽

2013 ◽

Author(s):

Andy Groves

Keyword(s):

Cell Differentiation ◽

Hair Cell ◽

Hedgehog Signaling ◽

Hair Cell Differentiation

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HIC1 Represses Atoh1 Transcription and Hair Cell Differentiation in the Cochlea

Stem Cell Reports ◽

10.1016/j.stemcr.2021.02.022 ◽

2021 ◽

Vol 16 (4) ◽

pp. 797-809

Author(s):

Dunia Abdul-Aziz ◽

Nicolai Hathiramani ◽

Lauren Phung ◽

Vittoria Sykopetrites ◽

Albert S.B. Edge

Keyword(s):

Cell Differentiation ◽

Hair Cell ◽

Hair Cell Differentiation

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Hes1 is a negative regulator of inner ear hair cell differentiation

Development ◽

10.1242/dev.127.21.4551 ◽

2000 ◽

Vol 127 (21) ◽

pp. 4551-4560 ◽

Cited By ~ 5

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.

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

eLife ◽

10.7554/elife.47613 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 3

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.

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

Cells ◽

10.3390/cells8050458 ◽

2019 ◽

Vol 8 (5) ◽

pp. 458 ◽

Cited By ~ 2

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.

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