scholarly journals Functional Role of Class III Myosins in Hair Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Joseph A. Cirilo ◽  
Laura K. Gunther ◽  
Christopher M. Yengo
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Atp Hydrolysis ◽  
Point Mutations ◽  
Special Focus ◽  
Myosin Isoforms ◽  
Class Iii ◽  
Myosin Motors ◽  
And Function

Cytoskeletal motors produce force and motion using the energy from ATP hydrolysis and function in a variety of mechanical roles in cells including muscle contraction, cargo transport, and cell division. Actin-based myosin motors have been shown to play crucial roles in the development and function of the stereocilia of auditory and vestibular inner ear hair cells. Hair cells can contain hundreds of stereocilia, which rely on myosin motors to elongate, organize, and stabilize their structure. Mutations in many stereocilia-associated myosins have been shown to cause hearing loss in both humans and animal models suggesting that each myosin isoform has a specific function in these unique parallel actin bundle-based protrusions. Here we review what is known about the classes of myosins that function in the stereocilia, with a special focus on class III myosins that harbor point mutations associated with delayed onset hearing loss. Much has been learned about the role of the two class III myosin isoforms, MYO3A and MYO3B, in maintaining the precise stereocilia lengths required for normal hearing. We propose a model for how class III myosins play a key role in regulating stereocilia lengths and demonstrate how their motor and regulatory properties are particularly well suited for this function. We conclude that ongoing studies on class III myosins and other stereocilia-associated myosins are extremely important and may lead to novel therapeutic strategies for the treatment of hearing loss due to stereocilia degeneration.

scholarly journals Essential Role of Sptan1 in Cochlear Hair Cell Morphology and Function Via Focal Adhesion Signaling

2021 ◽  
Author(s):  
Qingxiu Yao ◽  
Hui Wang ◽  
Hengchao Chen ◽  
Zhuangzhuang Li ◽  
Yumeng Jiang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cell ◽  
Focal Adhesion ◽  
Hair Cells ◽  
Focal Adhesions ◽  
Organ Of Corti ◽  
Cochlear Hair Cell ◽  
Cuticular Plate ◽  
And Function

AbstractHearing loss is the most common human sensory deficit. Hearing relies on stereocilia, inserted into the cuticular plate of hair cells (HCs), where they play an important role in the perception of sound and its transmission. Although numerous genes have been associated with hearing loss, the function of many hair cell genes has yet to be elucidated. Herein, we focused on nonerythroid spectrin αII (SPTAN1), abundant in the cuticular plate, surrounding the rootlets of stereocilia and along the plasma membrane. Interestingly, mice with HC-specific Sptan1 knockout exhibited rapid deafness, abnormal formation of stereocilia and cuticular plates, and loss of HCs from middle and apical turns of the cochlea during early postnatal stages. Additionally, Sptan1 deficiency led to the decreased spreading of House Ear Institute-Organ of Corti 1 cells, and induced abnormal formation of focal adhesions and integrin signaling in mouse HCs. Altogether, our findings highlight SPTAN1 as a critical molecule for HC stereocilia morphology and auditory function via regulation of focal adhesion signaling.

scholarly journals Caffeine Induces Autophagy and Apoptosis in Auditory Hair Cells via the SGK1/HIF-1α Pathway

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaomin Tang ◽  
Yuxuan Sun ◽  
Chenyu Xu ◽  
Xiaotao Guo ◽  
Jiaqiang Sun ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Hair Cells ◽  
Stria Vascularis ◽  
Spiral Ganglion ◽  
Organ Of Corti ◽  
Spiral Ganglion Neurons ◽  
Auditory Hair Cells ◽  
Qrt Pcr ◽  
Ganglion Neurons

Caffeine is being increasingly used in daily life, such as in drinks, cosmetics, and medicine. Caffeine is known as a mild stimulant of the central nervous system, which is also closely related to neurologic disease. However, it is unknown whether caffeine causes hearing loss, and there is great interest in determining the effect of caffeine in cochlear hair cells. First, we explored the difference in auditory brainstem response (ABR), organ of Corti, stria vascularis, and spiral ganglion neurons between the control and caffeine-treated groups of C57BL/6 mice. RNA sequencing was conducted to profile mRNA expression differences in the cochlea of control and caffeine-treated mice. A CCK-8 assay was used to evaluate the approximate concentration of caffeine. Flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting were performed to detect the effects of SGK1 in HEI-OC1 cells and basilar membranes. In vivo research showed that 120 mg/ kg caffeine injection caused hearing loss by damaging the organ of Corti, stria vascularis, and spiral ganglion neurons. RNA-seq results suggested that SGK1 might play a vital role in ototoxicity. To confirm our observations in vitro, we used the HEI-OC1 cell line, a cochlear hair cell-like cell line, to investigate the role of caffeine in hearing loss. The results of flow cytometry, TUNEL assay, immunocytochemistry, qRT-PCR, and Western blotting showed that caffeine caused autophagy and apoptosis via SGK1 pathway. We verified the interaction between SGK1 and HIF-1α by co-IP. To confirm the role of SGK1 and HIF-1α, GSK650394 was used as an inhibitor of SGK1 and CoCl2 was used as an inducer of HIF-1α. Western blot analysis suggested that GSK650394 and CoCl2 relieved the caffeine-induced apoptosis and autophagy. Together, these results indicated that caffeine induces autophagy and apoptosis in auditory hair cells via the SGK1/HIF-1α pathway, suggesting that caffeine may cause hearing loss. Additionally, our findings provided new insights into ototoxic drugs, demonstrating that SGK1 and its downstream pathways may be potential therapeutic targets for hearing research at the molecular level.

scholarly journals The Role of Glycocalyx and Caveolae in Vascular Homeostasis and Diseases

2021 ◽  
Vol 11 ◽  
Author(s):  
Simone Regina Potje ◽  
Tiago Dal-Cin Paula ◽  
Michele Paulo ◽  
Lusiane Maria Bendhack
Keyword(s):  
Nitric Oxide ◽  
Reactive Oxygen Species ◽  
Cardiovascular Diseases ◽  
Endothelial Glycocalyx ◽  
Special Focus ◽  
Oxygen Species ◽  
Vascular Homeostasis ◽  
Structure Synthesis ◽  
And Function

This review highlights recent findings about the role that endothelial glycocalyx and caveolae play in vascular homeostasis. We describe the structure, synthesis, and function of glycocalyx and caveolae in vascular cells under physiological and pathophysiological conditions. Special focus will be given in glycocalyx and caveolae that are associated with impaired production of nitric oxide (NO) and generation of reactive oxygen species (ROS). Such alterations could contribute to the development of cardiovascular diseases, such as atherosclerosis, and hypertension.

scholarly journals Cnr2 Is Important for Ribbon Synapse Maturation and Function in Hair Cells and Photoreceptors

2021 ◽  
Vol 14 ◽  
Author(s):  
Luis Colón-Cruz ◽  
Roberto Rodriguez-Morales ◽  
Alexis Santana-Cruz ◽  
Juan Cantres-Velez ◽  
Aranza Torrado-Tapias ◽  
...  
Keyword(s):  
Hair Cells ◽  
Cannabinoid Receptor ◽  
Sensory Information ◽  
Endocannabinoid System ◽  
Cannabinoid Receptor 2 ◽  
Ribbon Synapses ◽  
Sensory Epithelia ◽  
Synapse Maturation ◽  
And Function

The role of the cannabinoid receptor 2 (CNR2) is still poorly described in sensory epithelia. We found strong cnr2 expression in hair cells (HCs) of the inner ear and the lateral line (LL), a superficial sensory structure in fish. Next, we demonstrated that sensory synapses in HCs were severely perturbed in larvae lacking cnr2. Appearance and distribution of presynaptic ribbons and calcium channels (Cav1.3) were profoundly altered in mutant animals. Clustering of membrane-associated guanylate kinase (MAGUK) in post-synaptic densities (PSDs) was also heavily affected, suggesting a role for cnr2 for maintaining the sensory synapse. Furthermore, vesicular trafficking in HCs was strongly perturbed suggesting a retrograde action of the endocannabinoid system (ECs) via cnr2 that was modulating HC mechanotransduction. We found similar perturbations in retinal ribbon synapses. Finally, we showed that larval swimming behaviors after sound and light stimulations were significantly different in mutant animals. Thus, we propose that cnr2 is critical for the processing of sensory information in the developing larva.

scholarly journals Cilia in the developing zebrafish ear

2019 ◽  
Vol 375 (1792) ◽  
pp. 20190163 ◽  
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’.

Novel FERMT3 and PTPRQ Mutations Associated with Leukocyte Adhesion Deficiency-III and Sensorineural Hearing Loss

2021 ◽  
Author(s):  
Gabriela de Toledo Passos Candelaria ◽  
Alexandre de A. Antunes ◽  
Antonio C. Pastorino ◽  
Mayra de B. Dorna ◽  
Evelin A. Zanardo ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Sensorineural Hearing Loss ◽  
Hair Cells ◽  
Leukocyte Adhesion ◽  
Tyrosine Phosphatase ◽  
Sensorineural Hearing ◽  
Leukocyte Adhesion Deficiency ◽  
Brazilian Patient ◽  
And Function ◽  
Genotype Correlation

AbstractLeukocyte adhesion deficiency-III (LAD-III) is a rare genetic disease caused by defective integrin activation in hematopoietic cells due to mutations in the FERMT3 gene. The PTPRQ gene encodes the protein tyrosine phosphatase receptor Q and is essential for the normal maturation and function of hair bundle in the cochlea. Homozygous PTPRQ mutations impair the stereocilia in hair cells which lead to nonsyndromic sensorineural hearing loss (SNHL) with vestibular dysfunction. Here, we report two novel pathogenic homozygous mutations found in two genes, FERMT3 and PTPRQ, in a Brazilian patient with LAD-III and SNHL, which may develop our understanding of the phenotype–genotype correlation and prognosis of patients with these rare diseases.

P0400DECREASED REGULATORY B CELLS AND THEIR ASSOCIATION WITH CLINICAL RESPONSE IN PATIENTS WITH NEW ONSET LUPUS NEPHRITIS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Krishan Lal Gupta ◽  
Ivedita Girimaji ◽  
Aruna Rakha ◽  
Urvashi Kaundal ◽  
Raja Ramachandran ◽  
...  
Keyword(s):  
B Cells ◽  
Lupus Nephritis ◽  
Clinical Response ◽  
Newly Diagnosed ◽  
Class Iii ◽  
Peripheral Blood Mononuclear ◽  
Treg Number ◽  
Treatment Naïve ◽  
And Function

Abstract Background and Aims Studies in lupus nephritis (LN) have shown impairment in both T regulatory (Treg) number and function. However, the data on B regulatory (Breg) is limited in LN. Our objective was to study Breg and Treg populations in newly diagnosed treatment naïve LN and study their change after initiation of immunosuppression. Method Study included 25 patients of newly diagnosed LN of Class III (+V), IV (+V), V and 10 healthy controls (HC). Immunophenotyping was performed for peripheral blood mononuclear cell (PBMCs) samples using fluorochrome labelled monoclonal antibodies for Tregs (CD3+CD4+CD25hiCD127loFoxP3+) and Bregs (CD19+CD5+CD1dhi IL-10+). The cells were expressed as percentage of T and B cells. Each lymphocyte population was analysed at baseline, 2 and 6 months after initiation of immunosuppression which was given as per unit protocol. Results Bregs were significantly decreased compared to HC at baseline (p=0.002). With immunosuppression, Bregs showed significant increase at 2 and 6 months (p=0.008) and from baseline to 6 months (p=0.005). Bregs in responders significantly increased from 2 to 6 months (p= 0.017) and from baseline to 6 month (p=0.020), while they did not in non-responders. Tregs did not differ significantly from HC and did not show significant increase at 2 and 6 months, in both responders and non-responders. Conclusion Breg population in newly diagnosed LN was significantly reduced and increased significantly with immunosuppression. Bregs had an association with renal remission. This underscores the potential role of Bregs in the pathophysiology of LN and their association with clinical response. This could aid in the design of new immunotherapies for treatment of lupus nephritis.

scholarly journals Elmod3 knockout leads to progressive hearing loss and abnormalities in cochlear hair cell stereocilia

2019 ◽  
Vol 28 (24) ◽  
pp. 4103-4112 ◽  
Author(s):  
Wu Li ◽  
Yong Feng ◽  
Anhai Chen ◽  
Taoxi Li ◽  
Sida Huang ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Actin Cytoskeleton ◽  
Hearing Impairment ◽  
Hair Cells ◽  
Organ Of Corti ◽  
Vestibular Function ◽  
Outer Hair Cells ◽  
Auditory Function ◽  
Cochlear Hair Cells

Abstract ELMOD3, an ARL2 GTPase-activating protein, is implicated in causing hearing impairment in humans. However, the specific role of ELMOD3 in auditory function is still far from being elucidated. In the present study, we used the CRISPR/Cas9 technology to establish an Elmod3 knockout mice line in the C57BL/6 background (hereinafter referred to as Elmod3−/− mice) and investigated the role of Elmod3 in the cochlea and auditory function. Elmod3−/− mice started to exhibit hearing loss from 2 months of age, and the deafness progressed with aging, while the vestibular function of Elmod3−/− mice was normal. We also observed that Elmod3−/− mice showed thinning and receding hair cells in the organ of Corti and much lower expression of F-actin cytoskeleton in the cochlea compared with wild-type mice. The deafness associated with the mutation may be caused by cochlear hair cells dysfunction, which manifests with shortening and fusion of inner hair cells stereocilia and progressive degeneration of outer hair cells stereocilia. Our finding associates Elmod3 deficiencies with stereocilia dysmorphologies and reveals that they might play roles in the actin cytoskeleton dynamics in cochlear hair cells, and thus relate to hearing impairment.

scholarly journals Filling the Silent Void: Genetic Therapies for Hearing Impairment

2012 ◽  
Vol 2012 ◽  
pp. 1-9
Author(s):  
Joel Sng ◽  
Thomas Lufkin
Keyword(s):  
Inner Ear ◽  
Hearing Impairment ◽  
Hair Cells ◽  
Genetic Disorders ◽  
Environmental Damage ◽  
Inner Ear Development ◽  
Sensory Hair Cells ◽  
And Function ◽  
Function Potential

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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