scholarly journals Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

2021 ◽  
Vol 22 (12) ◽  
pp. 6497
Author(s):  
Anna Ghilardi ◽  
Alberto Diana ◽  
Renato Bacchetta ◽  
Nadia Santo ◽  
Miriam Ascagni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Hair Cells ◽  
Muscle Fibers ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Inner Ear Development ◽  
Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

scholarly journals Knockout of mafba Causes Inner-Ear Developmental Defects in Zebrafish via the Impairment of Proliferation and Differentiation of Ionocyte Progenitor Cells

Biomedicines ◽  
2021 ◽  
Vol 9 (11) ◽  
pp. 1699
Author(s):  
Xiang Chen ◽  
Yuwen Huang ◽  
Pan Gao ◽  
Yuexia Lv ◽  
Danna Jia ◽  
...  
Keyword(s):  
Inner Ear ◽  
Ionic Channel ◽  
Structural Defects ◽  
Sound Stimulation ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Ear Development ◽  
Cycle Arrest ◽  
Inner Ear Development ◽  
Loss Of Hearing

Zebrafish is an excellent model for exploring the development of the inner ear. Its inner ear has similar functions to that of humans, specifically in the maintenance of hearing and balance. Mafba is a component of the Maf transcription factor family. It participates in multiple biological processes, but its role in inner-ear development remains poorly understood. In this study, we constructed a mafba knockout (mafba−/−) zebrafish model using CRISPR/Cas9 technology. The mafba−/− mutant inner ear displayed severe impairments, such as enlarged otocysts, smaller or absent otoliths, and insensitivity to sound stimulation. The proliferation of p63+ epidermal stem cells and dlc+ ionocyte progenitors was inhibited in mafba−/− mutants. Moreover, the results showed that mafba deletion induces the apoptosis of differentiated K+-ATPase-rich (NR) cells and H+-ATPase-rich (HR) cells. The activation of p53 apoptosis and G0/G1 cell cycle arrest resulted from DNA damage in the inner-ear region, providing a mechanism to account for the inner ear deficiencies. The loss of homeostasis resulting from disorders of ionocyte progenitors resulted in structural defects in the inner ear and, consequently, loss of hearing. In conclusion, the present study elucidated the function of ionic channel homeostasis and inner-ear development using a zebrafish Mafba model and clarified the possible physiological roles.

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 Role of microRNAs in inner ear development and hearing loss

Gene ◽  
2019 ◽  
Vol 686 ◽  
pp. 49-55 ◽  
Author(s):  
Rahul Mittal ◽  
George Liu ◽  
Sai P. Polineni ◽  
Nicole Bencie ◽  
Denise Yan ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Ear Development ◽  
Inner Ear Development

CHD7 regulates otic lineage differentiation and deafness gene expression in human inner ear organoids

2021 ◽  
Author(s):  
Jing Nie ◽  
Yoshitomo Ueda ◽  
Alexander Solivais ◽  
Eri Hashino
Keyword(s):  
Gene Expression ◽  
Inner Ear ◽  
Chromatin Remodeling ◽  
Hair Cells ◽  
Critical Role ◽  
Transcriptome Profiling ◽  
Underlying Mechanism ◽  
Lineage Differentiation ◽  
Deafness Gene ◽  
Human Inner Ear

Abstract Mutations in the chromatin remodeling enzyme CHD7 cause CHARGE syndrome, which affects multiple organs including the inner ear. We investigated how CHD7 mutations affect otic development in human inner ear organoids. We found loss of CHD7 or its chromatin remodeling activity leads to complete absence of hair cells and supporting cells, which can be explained by dysregulation of key otic development-associated genes in mutant otic progenitors. Further analysis of the mutant otic progenitors suggested that CHD7 can regulate otic genes through a chromatin remodeling-independent mechanism. Results from transcriptome profiling of hair cells revealed disruption of deafness gene expression as a potential underlying mechanism of CHARGE-associated sensorineural hearing loss. Notably, co-differentiating CHD7 knockout and wild-type cells in chimeric organoids partially rescued mutant phenotypes by restoring otherwise severely dysregulated otic genes. Taken together, our results suggest that CHD7 plays a critical role in regulating human otic lineage differentiation and deafness gene expression.

scholarly journals Evidence for a dynorphin-mediated inner ear immune/inflammatory response and glutamate-induced neural excitotoxicity: an updated analysis

2019 ◽  
Vol 122 (4) ◽  
pp. 1421-1460
Author(s):  
Tony L. Sahley ◽  
David J. Anderson ◽  
Michael D. Hammonds ◽  
Karthik Chandu ◽  
Frank E. Musiek
Keyword(s):  
Hearing Loss ◽  
Brain Stem ◽  
Inner Ear ◽  
Hair Cells ◽  
Oxidative Stress Response ◽  
Neural Systems ◽  
Type I ◽  
Excitatory Neurotransmitter ◽  
Axon Terminals ◽  
Cochlear Hearing Loss

Acoustic overstimulation (AOS) is defined as the stressful overexposure to high-intensity sounds. AOS is a precipitating factor that leads to a glutamate (GLU)-induced Type I auditory neural excitotoxicity and an activation of an immune/inflammatory/oxidative stress response within the inner ear, often resulting in cochlear hearing loss. The dendrites of the Type I auditory neural neurons that innervate the inner hair cells (IHCs), and respond to the IHC release of the excitatory neurotransmitter GLU, are themselves directly innervated by the dynorphin (DYN)-bearing axon terminals of the descending brain stem lateral olivocochlear (LOC) system. DYNs are known to increase GLU availability, potentiate GLU excitotoxicity, and induce superoxide production. DYNs also increase the production of proinflammatory cytokines by modulating immune/inflammatory signal transduction pathways. Evidence is provided supporting the possibility that the GLU-mediated Type I auditory neural dendritic swelling, inflammation, excitotoxicity, and cochlear hearing loss that follow AOS may be part of a brain stem-activated, DYN-mediated cascade of inflammatory events subsequent to a LOC release of DYNs into the cochlea. In support of a DYN-mediated cascade of events are established investigations linking DYNs to the immune/inflammatory/excitotoxic response in other neural systems.

scholarly journals Celsr1 coordinates the planar polarity of vestibular hair cells during inner ear development

2017 ◽  
Vol 423 (2) ◽  
pp. 126-137 ◽  
Author(s):  
Jeremy S. Duncan ◽  
Michelle L. Stoller ◽  
Andrew F. Francl ◽  
Fadel Tissir ◽  
Danelle Devenport ◽  
...  
Keyword(s):  
Inner Ear ◽  
Hair Cells ◽  
Planar Polarity ◽  
Ear Development ◽  
Vestibular Hair Cells ◽  
Inner Ear Development

Auditory and vestibular hair cell stereocilia: relationship between functionality and inner ear disease

2011 ◽  
Vol 125 (10) ◽  
pp. 991-1003 ◽  
Author(s):  
R R Ciuman
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Inner Ear ◽  
Frequency Selectivity ◽  
Cellular Structures ◽  
Hereditary Deafness ◽  
Mechanoelectrical Transduction ◽  
Cochlear Amplification ◽  
Inner Ear Disease ◽  
Syndromic Hearing Loss

AbstractThe stereocilia of the inner ear are unique cellular structures which correlate anatomically with distinct cochlear functions, including mechanoelectrical transduction, cochlear amplification, adaptation, frequency selectivity and tuning. Their function is impaired by inner ear stressors, by various types of hereditary deafness, syndromic hearing loss and inner ear disease (e.g. Ménière's disease). The anatomical and physiological characteristics of stereocilia are discussed in relation to inner ear malfunctions.

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

Development ◽  
2007 ◽  
Vol 134 (24) ◽  
pp. 4405-4415 ◽  
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

scholarly journals Effects of Microbubble Size on Ultrasound-Mediated Gene Transfection in Auditory Cells

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Ai-Ho Liao ◽  
Yi-Lei Hsieh ◽  
Hsin-Chiao Ho ◽  
Hang-Kang Chen ◽  
Yi-Chun Lin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Hearing Loss ◽  
Gene Transfer ◽  
Inner Ear ◽  
Hair Cells ◽  
Gene Transfection ◽  
Effective Technique ◽  
Size Dependent ◽  
Genes Encoding

Gene therapy for sensorineural hearing loss has recently been used to insert genes encoding functional proteins to preserve, protect, or even regenerate hair cells in the inner ear. Our previous study demonstrated a microbubble- (MB-)facilitated ultrasound (US) technique for delivering therapeutic medication to the inner ear. The present study investigated whether MB-US techniques help to enhance the efficiency of gene transfection by means of cationic liposomes on HEI-OC1 auditory cells and whether MBs of different sizes affect such efficiency. Our results demonstrated that the size of MBs was proportional to the concentration of albumin or dextrose. At a constant US power density, using 0.66, 1.32, and 2.83 μm albumin-shelled MBs increased the transfection rate as compared to the control by 30.6%, 54.1%, and 84.7%, respectively; likewise, using 1.39, 2.12, and 3.47 μm albumin-dextrose-shelled MBs increased the transfection rates by 15.9%, 34.3%, and 82.7%, respectively. The results indicate that MB-US is an effective technique to facilitate gene transfer on auditory cellsin vitro. Such size-dependent MB oscillation behavior in the presence of US plays a role in enhancing gene transfer, and by manipulating the concentration of albumin or dextrose, MBs of different sizes can be produced.

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