Filling the Silent Void: Genetic Therapies for Hearing Impairment

The inner ear cytoarchitecture forms one of the most intricate and delicate organs in the human body and is vulnerable to the effects of genetic disorders, aging, and environmental damage. Owing to the inability of the mammalian cochlea to regenerate sensory hair cells, the loss of hair cells is a leading cause of deafness in humans. Millions of individuals worldwide are affected by the emotionally and financially devastating effects of hearing impairment (HI). This paper provides a brief introduction into the key role of genes regulating inner ear development and function. Potential future therapies that leverage on an improved understanding of these molecular pathways are also described in detail.

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Cross-regulation of Ngn1 and Math1 coordinates the production of neurons and sensory hair cells during inner ear development

Development ◽

10.1242/dev.009118 ◽

2007 ◽

Vol 134 (24) ◽

pp. 4405-4415 ◽

Cited By ~ 139

Author(s):

S. Raft ◽

E. J. Koundakjian ◽

H. Quinones ◽

C. S. Jayasena ◽

L. V. Goodrich ◽

...

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Sensory Hair ◽

Ear Development ◽

Inner Ear Development ◽

Sensory Hair Cells

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Cilia in the developing zebrafish ear

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2019.0163 ◽

2019 ◽

Vol 375 (1792) ◽

pp. 20190163 ◽

Cited By ~ 5

Author(s):

Tanya T. Whitfield

Keyword(s):

Hair Cells ◽

Otic Vesicle ◽

Sensory Hair ◽

Ciliary Motility ◽

Extracellular Signals ◽

Sensory Hair Cell ◽

Sensory Hair Cells ◽

And Function ◽

Cellular Compartments

The inner ear, which mediates the senses of hearing and balance, derives from a simple ectodermal vesicle in the vertebrate embryo. In the zebrafish, the otic placode and vesicle express a whole suite of genes required for ciliogenesis and ciliary motility. Every cell of the otic epithelium is ciliated at early stages; at least three different ciliary subtypes can be distinguished on the basis of length, motility, genetic requirements and function. In the early otic vesicle, most cilia are short and immotile. Long, immotile kinocilia on the first sensory hair cells tether the otoliths, biomineralized aggregates of calcium carbonate and protein. Small numbers of motile cilia at the poles of the otic vesicle contribute to the accuracy of otolith tethering, but neither the presence of cilia nor ciliary motility is absolutely required for this process. Instead, otolith tethering is dependent on the presence of hair cells and the function of the glycoprotein Otogelin. Otic cilia or ciliary proteins also mediate sensitivity to ototoxins and coordinate responses to extracellular signals. Other studies are beginning to unravel the role of ciliary proteins in cellular compartments other than the kinocilium, where they are important for the integrity and survival of the sensory hair cell. This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.

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R449 – The Role of DPZF in Inner Ear Development and Function

Otolaryngology ◽

10.1016/j.otohns.2008.05.605 ◽

2008 ◽

Vol 139 (2_suppl) ◽

pp. P195-P195

Author(s):

Gao Xia

Keyword(s):

Electron Microscopy ◽

Scanning Electron Microscopy ◽

Inner Ear ◽

Hair Cells ◽

Otoacoustic Emissions ◽

Auditory Brainstem ◽

Auditory Brainstem Responses ◽

Inner Ear Development ◽

Scanning Electron

Problem The dendritic cell-derived BTB/POZ zinc finger (DPZF) protein belongs to the C2H2 zinc finger protein transcription factor family. It is localized on chromosome 3 and widely expressed in hematopoietic tissues, including human dendritic cells (DC), monocytes, B cells and T cells. DPZF null mice (DPZF-/-) exhibit a circling phenotype, suggestive of an inner ear defect. Here, we present our work on the role of DPZF in hearing defects. Methods We used auditory brainstem responses (ABR) and distortion production otoacoustic emissions (DPOAEs) to test the hearing function of DPZF-/- mice, then gross observation and histopathology analysis including serial sections and scanning electron microscopy were performed to exam the cochlea of DPZF-/- mice. Results Auditory brainstem responses (ABR) and distortion production otoacoustic emissions (DPOAEs) showed that DPZF-/-mice were completely deaf. Disorganized and fewer hair cells of the Corti organ in DPZF-/- mice were identified by scanning electron microscopy. Besides, although the hair cells of the utricle and saccule were grossly normal, the stereocilia were greatly reduced in number. Further more, lipofuscin was seen in the stria vascularis with the amount of which increased with age. Conclusion The impaired hearing and balance function and the morphological abnormalities of inner ears are caused by the deletion of DPZF gene. Significance DPZF gene may participates in regulating inner ear development and the DPZF null mice may serve as a new disease model of hearing loss. Support This work was supported by the ground of Jiangsu Province Famous Doctor Project(RC2007010).

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The Role of FoxG1 in the Inner Ear

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.614954 ◽

2020 ◽

Vol 8 ◽

Author(s):

Yanyan Ding ◽

Wei Meng ◽

Weijia Kong ◽

Zuhong He ◽

Renjie Chai

Keyword(s):

Hearing Loss ◽

Inner Ear ◽

Signal Transmission ◽

Sensorineural Deafness ◽

Auditory Signal ◽

Forkhead Box ◽

Inner Ear Development ◽

Ototoxic Drugs ◽

And Function

Sensorineural deafness is mainly caused by damage to the tissues of the inner ear, and hearing impairment has become an increasingly serious global health problem. When the inner ear is abnormally developed or is damaged by inflammation, ototoxic drugs, or blood supply disorders, auditory signal transmission is inhibited resulting in hearing loss. Forkhead box G1 (FoxG1) is an important nuclear transcriptional regulator, which is related to the differentiation, proliferation, development, and survival of cells in the brain, telencephalon, inner ear, and other tissues. Previous studies have shown that when FoxG1 is abnormally expressed, the development and function of inner ear hair cells is impaired. This review discusses the role and regulatory mechanism of FoxG1 in inner ear tissue from various aspects – such as the effect on inner ear development, the maintenance of inner ear structure and function, and its role in the inner ear when subjected to various stimulations or injuries – in order to explain the potential significance of FoxG1 as a new target for the treatment of hearing loss.

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Dlx3b/4b is required for early-born but not later-forming sensory hair cells during zebrafish inner ear development

Biology Open ◽

10.1242/bio.026211 ◽

2017 ◽

Vol 6 (9) ◽

pp. 1270-1278 ◽

Cited By ~ 4

Author(s):

Simone Schwarzer ◽

Sandra Spieß ◽

Michael Brand ◽

Stefan Hans

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Sensory Hair ◽

Ear Development ◽

Inner Ear Development ◽

Sensory Hair Cells

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let-7 miRNAs inhibit CHD7 expression and control auditory-sensory progenitor cell behavior in the developing inner ear

Development ◽

10.1242/dev.183384 ◽

2020 ◽

Vol 147 (15) ◽

pp. dev183384

Author(s):

Lale Evsen ◽

Xiaojun Li ◽

Shuran Zhang ◽

Sharjil Razin ◽

Angelika Doetzlhofer

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Progenitor Cell ◽

Charge Syndrome ◽

Basilar Papilla ◽

Sensory Hair Cells ◽

Evolutionarily Conserved ◽

Auditory Organ ◽

And Control

ABSTRACTThe evolutionarily conserved lethal-7 (let-7) microRNAs (miRNAs) are well-known activators of proliferative quiescence and terminal differentiation. However, in the murine auditory organ, let-7g overexpression delays the differentiation of mechano-sensory hair cells (HCs). To address whether the role of let-7 in auditory-sensory differentiation is conserved among vertebrates, we manipulated let-7 levels within the chicken auditory organ: the basilar papilla. Using a let-7 sponge construct to sequester let-7 miRNAs, we found that endogenous let-7 miRNAs are essential for limiting the self-renewal of HC progenitor cells. Furthermore, let-7b overexpression experiments revealed that, similar to mice, higher than normal let-7 levels slow/delay HC differentiation. Finally, we identify CHD7, a chromatin remodeler, as a candidate for mediating the repressive function of let-7 in HC differentiation and inner ear morphogenesis. Our analysis uncovered an evolutionarily conserved let-7-5p-binding site within the chicken Chd7 gene and its human and murine homologs, and we show that let-7g overexpression in mice limits CHD7 expression in the developing inner ear, retina and brain. Haploinsufficiency of CHD7 in humans causes CHARGE syndrome and attenuation of let-7 function may be an effective method for treating CHD7 deficiency.

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Plastin 1 widens stereocilia by transforming actin filament packing from hexagonal to liquid

The Journal of Cell Biology ◽

10.1083/jcb.201606036 ◽

2016 ◽

Vol 215 (4) ◽

pp. 467-482 ◽

Cited By ~ 21

Author(s):

Jocelyn F. Krey ◽

Evan S. Krystofiak ◽

Rachel A. Dumont ◽

Sarath Vijayakumar ◽

Dongseok Choi ◽

...

Keyword(s):

Inner Ear ◽

Hair Cells ◽

Double Mutant ◽

Structure And Function ◽

Wild Type ◽

Auditory Function ◽

Hexagonal Packing ◽

Sensory Hair Cells ◽

Actin Protrusions ◽

And Function

With their essential role in inner ear function, stereocilia of sensory hair cells demonstrate the importance of cellular actin protrusions. Actin packing in stereocilia is mediated by cross-linkers of the plastin, fascin, and espin families. Although mice lacking espin (ESPN) have no vestibular or auditory function, we found that mice that either lacked plastin 1 (PLS1) or had nonfunctional fascin 2 (FSCN2) had reduced inner ear function, with double-mutant mice most strongly affected. Targeted mass spectrometry indicated that PLS1 was the most abundant cross-linker in vestibular stereocilia and the second most abundant protein overall; ESPN only accounted for ∼15% of the total cross-linkers in bundles. Mouse utricle stereocilia lacking PLS1 were shorter and thinner than wild-type stereocilia. Surprisingly, although wild-type stereocilia had random liquid packing of their actin filaments, stereocilia lacking PLS1 had orderly hexagonal packing. Although all three cross-linkers are required for stereocilia structure and function, PLS1 biases actin toward liquid packing, which allows stereocilia to grow to a greater diameter.

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