SCN11A Gene Deletion Causes Sensorineural Hearing Loss by Impairing the Ribbon Synapses and Auditory Nerves

2020 ◽  
Author(s):  
Mian Zu ◽  
Wei-wei Guo ◽  
Tao Cong ◽  
Fei Ji ◽  
Shi-li Zhang ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Hair Cells ◽  
Gene Deletion ◽  
Cochlear Microphonics ◽  
Wild Type ◽  
Nociceptive Neurons ◽  
Quantitative Expression ◽  
Ribbon Synapses ◽  
Auditory Nerves

Abstract Background: The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice. Results: Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice in the basal turn was also lower than WT, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Nav1.9 KO mice showed higher and progressive ABR threshold at 16 kHz, a significant increase in CAP thresholds, while no changes in cochlear microphonics (CM). Conclusions: These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.

scholarly journals SCN11A gene deletion causes sensorineural hearing loss by impairing the ribbon synapses and auditory nerves

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Mian Zu ◽  
Wei-Wei Guo ◽  
Tao Cong ◽  
Fei Ji ◽  
Shi-Li Zhang ◽  
...  
Keyword(s):  
Sodium Channels ◽  
Hair Cells ◽  
Gene Deletion ◽  
Peripheral Inflammation ◽  
Wild Type ◽  
Nociceptive Neurons ◽  
Quantitative Expression ◽  
Ribbon Synapses ◽  
Auditory Nerves

Abstract Background The SCN11A gene, encoded Nav1.9 TTX resistant sodium channels, is a main effector in peripheral inflammation related pain in nociceptive neurons. The role of SCN11A gene in the auditory system has not been well characterized. We therefore examined the expression of SCN11A in the murine cochlea, the morphological and physiological features of Nav1.9 knockout (KO) ICR mice. Results Nav1.9 expression was found in the primary afferent endings beneath the inner hair cells (IHCs). The relative quantitative expression of Nav1.9 mRNA in modiolus of wild-type (WT) mice remains unchanged from P0 to P60. The number of presynaptic CtBP2 puncta in Nav1.9 KO mice was significantly lower than WT. In addition, the number of SGNs in Nav1.9 KO mice was also less than WT in the basal turn, but not in the apical and middle turns. There was no lesion in the somas and stereocilia of hair cells in Nav1.9 KO mice. Furthermore, Nav1.9 KO mice showed higher and progressive elevated ABR threshold at 16 kHz, and a significant increase in CAP thresholds. Conclusions These data suggest a role of Nav1.9 in regulating the function of ribbon synapses and the auditory nerves. The impairment induced by Nav1.9 gene deletion mimics the characters of cochlear synaptopathy.

scholarly journals Deletion of Kcnj16 in Mice Does Not Alter Auditory Function

2021 ◽  
Vol 9 ◽  
Author(s):  
Jun Lv ◽  
Xiaolong Fu ◽  
Yige Li ◽  
Guodong Hong ◽  
Peipei Li ◽  
...  
Keyword(s):  
Hair Cells ◽  
Sensory Transduction ◽  
Wild Type ◽  
Auditory Function ◽  
Ribbon Synapses ◽  
Ear Morphology ◽  
Main Charge ◽  
Significant Difference ◽  
Endolymphatic Potential

Endolymphatic potential (EP) is the main driving force behind the sensory transduction of hearing, and K+ is the main charge carrier. Kir5.1 is a K+ transporter that plays a significant role in maintaining EP homeostasis, but the expression pattern and role of Kir5.1 (which is encoded by the Kcnj16 gene) in the mouse auditory system has remained unclear. In this study, we found that Kir5.1 was expressed in the mouse cochlea. We checked the inner ear morphology and measured auditory function in Kcnj16–/– mice and found that loss of Kcnj16 did not appear to affect the development of hair cells. There was no significant difference in auditory function between Kcnj16–/– mice and wild-type littermates, although the expression of Kcnma1, Kcnq4, and Kcne1 were significantly decreased in the Kcnj16–/– mice. Additionally, no significant differences were found in the number or distribution of ribbon synapses between the Kcnj16–/– and wild-type mice. In summary, our results suggest that the Kcnj16 gene is not essential for auditory function in mice.

scholarly journals The Role of Prestin in the Generation of Electrically Evoked Otoacoustic Emissions in Mice

2008 ◽  
Vol 99 (4) ◽  
pp. 1607-1615 ◽  
Author(s):  
Markus Drexl ◽  
Marcia M. Mellado Lagarde ◽  
Jian Zuo ◽  
Andrei N. Lukashkin ◽  
Ian J. Russell
Keyword(s):  
Hair Cells ◽  
Otoacoustic Emissions ◽  
Temporal Structure ◽  
Organ Of Corti ◽  
Outer Hair Cells ◽  
Tectorial Membrane ◽  
Wild Type ◽  
Short Delay ◽  
Delay Component

Electrically evoked otoacoustic emissions are sounds emitted from the inner ear when alternating current is injected into the cochlea. Their temporal structure consists of short- and long-delay components and they have been attributed to the motile responses of the sensory-motor outer hair cells of the cochlea. The nature of these motile responses is unresolved and may depend on either somatic motility, hair bundle motility, or both. The short-delay component persists after almost complete elimination of outer hair cells. Outer hair cells are thus not the sole generators of electrically evoked otoacoustic emissions. We used prestin knockout mice, in which the motor protein prestin is absent from the lateral walls of outer hair cells, and Tecta ΔENT/ΔENT mice, in which the tectorial membrane, a structure with which the hair bundles of outer hair cells normally interact, is vestigial and completely detached from the organ of Corti. The amplitudes and delay spectra of electrically evoked otoacoustic emissions from Tecta ΔENT/ΔENT and Tecta +/+ mice are very similar. In comparison with prestin +/+ mice, however, the short-delay component of the emission in prestin −/− mice is dramatically reduced and the long-delay component is completely absent. Emissions are completely suppressed in wild-type and Tecta ΔENT/ΔENT mice at low stimulus levels, when prestin-based motility is blocked by salicylate. We conclude that near threshold, the emissions are generated by prestin-based somatic motility.

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.

Abstract 126: Gene Deletion of Dipeptidyl Peptidase I Reduces Myocyte Loss and Preserves Cardiac Function After Myocardial Ischemia-Reperfusion Injury

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Zhao Qi ◽  
Mikhail Kolpakov ◽  
Bahman Hooshdaran ◽  
Khadija Rafiq ◽  
Xinji Guo ◽  
...  
Keyword(s):  
Myocardial Ischemia ◽  
Cardiac Function ◽  
Reperfusion Injury ◽  
Cardiac Remodeling ◽  
Serine Proteases ◽  
Gene Deletion ◽  
Cathepsin G ◽  
Wild Type ◽  
Myocyte Apoptosis

Introduction and Hypothesis: Chronic inflammation predisposes tissue to adverse cardiac remodeling and contributes to heart failure (HF) progression. The mechanisms whereby inflammation contributes to cardiac remodeling after cardiac injury has largely focused on action of reactive oxygen species and cytokines/chemokines and their role on myocyte growth and extracellular matrix (ECM) remodeling. However, the role of inflammatory proteases on myocyte loss and adverse cardiac remodeling has not been studied and are the focus of this study. Methods and Results: We subjected wild type and mice lacking Dipeptidyl peptidase I (DPPI), a lysosomal enzyme involved in the cleavage and activation of major inflammatory serine proteases, to myocardial ischemia for 30 min followed by reperfusion for 24hrs (IRI) and assessed the role of DPPI gene deletion on inflammatory proteases activation, myocyte apoptosis and cardiac remodeling and function. DPPI KO mice show markedly reduced inflammatory serine protease activity in response to myocardial IRI compared to wild type mice. DPPI deletion also markedly reduced myocyte apoptosis, limited infarct size and improved cardiac function in response to IRI. The role of inflammatory serine proteases in cardiac remodeling was further demonstrated after in-vivo cardiac transfer of cathepsin G, a neutrophil derived serine protease that has been shown to induce myocyte death in-vitro. Mice with cathepsin G injection for 5 days show increased interstitial collagen degradation and myocyte apoptosis and presented cardiac dilatation and contractile dysfunction. Conclusions: These findings reveal the role of DPPI as a key mediator of postischemic/reperfusion injury and show that inflammatory derived proteases contribute to the pathological cardiac remodeling and dysfunction.

Physiologically silent sodium channels in mammalian outer hair cells

1994 ◽  
Vol 72 (2) ◽  
pp. 1037-1040 ◽  
Author(s):  
C. M. Witt ◽  
H. Y. Hu ◽  
W. E. Brownell ◽  
D. Bertrand
Keyword(s):  
Sodium Channels ◽  
Hair Cells ◽  
Sodium Current ◽  
High Sensitivity ◽  
Outer Hair Cells ◽  
Inward Current ◽  
Cell Recording ◽  
Voltage Dependent

1. Voltage-dependent properties of isolated guinea pig outer hair cells (OHCs) were investigated using whole-cell recording. An inward current was detected in approximately 10% of the cells. This inward current was identified as belonging to the voltage-activated sodium current family on the basis of its high sensitivity to tetrodotoxin and the effect of substitution of impermeant ions. Although this is the first report of a sodium current in the mammalian cochlea, it differs from the classical neuronal sodium current by having a variable magnitude from cell to cell and an inactivation that is shifted to hyperpolarized potentials. The sensory processing role of hair cells in general and outer hair cells in particular could be disrupted by the presence of a regenerative voltage-dependent current. The functional role of the OHC sodium channels is puzzling, particularly as they may be silent in vivo.

scholarly journals Gene deletion reveals roles for annexin A1 in the regulation of lipolysis and IL-6 release in epididymal adipose tissue

2006 ◽  
Vol 291 (6) ◽  
pp. E1264-E1273 ◽  
Author(s):  
James P. Warne ◽  
Christopher D. John ◽  
Helen C. Christian ◽  
John F. Morris ◽  
Roderick J. Flower ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Gene Deletion ◽  
Cell Number ◽  
Receptor Expression ◽  
Epididymal Adipose Tissue ◽  
Wild Type ◽  
Inhibitory Effects ◽  
Tissue Mass

In this study, epididymal adipose tissue from male annexin 1 (ANXA1)-null and wild-type control mice were used to explore the potential role of ANXA1 in adipocyte biology. ANXA1 was detected by Western blot analysis in wild-type tissue and localized predominantly to the stromal-vascular compartment. Epididymal fat pad mass was reduced by ANXA1 gene deletion, but adipocyte size was unchanged, suggesting that ANXA1 is required for the maintenance of adipocyte and/or preadipocyte cell number. Epididymal tissue from wild-type mice responded in vitro to noradrenaline and isoprenaline with increased glycerol release, reduced IL-6 release, and increased cAMP accumulation. Qualitatively similar but significantly attenuated responses to the catecholamines were observed in tissue from ANXA1-null mice, an effect that was not associated with changes in β-adrenoceptor mRNA expression. Lipopolysaccharide (LPS) also stimulated lipolysis in vitro, but its effects were muted by ANXA1 gene deletion. By contrast, LPS failed to influence IL-6 release from wild-type tissue but stimulated the release of the cytokine from tissue from ANXA1-null mice. ANXA1 gene deletion did not affect glucocorticoid receptor expression or the ability of dexamethasone to suppress catecholamine-induced lipolysis. It did, however, augment IL-6 expression and modify the inhibitory effects of glucocorticoids on IL-6 release. Collectively, these studies suggest that ANXA1 supports aspects of adipose tissue mass and alters the sensitivity of epididymal adipose tissue to catecholamines, glucocorticoids, and LPS, thereby modulating lipolysis and IL-6 release.

scholarly journals The role of transmembrane channel–like proteins in the operation of hair cell mechanotransducer channels

2013 ◽  
Vol 142 (5) ◽  
pp. 493-505 ◽  
Author(s):  
Kyunghee X. Kim ◽  
Maryline Beurg ◽  
Carole M. Hackney ◽  
David N. Furness ◽  
Shanthini Mahendrasingam ◽  
...  
Keyword(s):  
Hair Cells ◽  
Hair Bundle ◽  
Wild Type ◽  
Cochlear Hair Cells ◽  
Transmembrane Channel ◽  
Protein Partners ◽  
Tip Link ◽  
Lower Permeability ◽  
Precise Role

Sound stimuli elicit movement of the stereocilia that make up the hair bundle of cochlear hair cells, putting tension on the tip links connecting the stereocilia and thereby opening mechanotransducer (MT) channels. Tmc1 and Tmc2, two members of the transmembrane channel–like family, are necessary for mechanotransduction. To assess their precise role, we recorded MT currents elicited by hair bundle deflections in mice with null mutations of Tmc1, Tmc2, or both. During the first postnatal week, we observed a normal MT current in hair cells lacking Tmc1 or Tmc2; however, in the absence of both isoforms, we recorded a large MT current that was phase-shifted 180°, being evoked by displacements of the hair bundle away from its tallest edge rather than toward it as in wild-type hair cells. The anomalous MT current in hair cells lacking Tmc1 and Tmc2 was blocked by FM1-43, dihydrostreptomycin, and extracellular Ca2+ at concentrations similar to those that blocked wild type. MT channels in the double knockouts carried Ca2+ with a lower permeability than wild-type or single mutants. The MT current in double knockouts persisted during exposure to submicromolar Ca2+, even though this treatment destroyed the tip links. We conclude that the Tmc isoforms do not themselves constitute the MT channel but are essential for targeting and interaction with the tip link. Changes in the MT conductance and Ca2+ permeability observed in the absence of Tmc1 mutants may stem from loss of interaction with protein partners in the transduction complex.

scholarly journals Role of Exopolygalacturonase-Related Genes in Potato-Verticillium dahliae Interaction

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 642
Author(s):  
Xiaohan Zhu ◽  
Mohammad Sayari ◽  
Fouad Daayf
Keyword(s):  
Verticillium Dahliae ◽  
Crop Production ◽  
Gene Deletion ◽  
Subtractive Hybridization ◽  
Full Genome ◽  
Wild Type ◽  
Leaf Extracts ◽  
Potato Leaf ◽  
Pectinase Activity

Verticillium dahliae is a hemibiotrophic pathogen responsible for great losses in dicot crop production. An ExoPG gene (VDAG_03463,) identified using subtractive hybridization/cDNA-AFLP, showed higher expression levels in highly aggressive than in weakly aggressive V. dahliae isolates. We used a vector-free split-marker recombination method with PEG-mediated protoplast to delete the ExoPG gene in V. dahliae. This is the first instance of using this method for V. dahliae transformation. Only two PCR steps and one transformation step were required, markedly reducing the necessary time for gene deletion. Six mutants were identified. ExoPG expressed more in the highly aggressive than in the weakly aggressive isolate in response to potato leaf and stem extracts. Its expression increased in both isolates during infection, with higher levels in the highly aggressive isolate at early infection stages. The disruption of ExoPG did not influence virulence, nor did it affect total exopolygalacturonase activity in V. dahliae. Full genome analysis showed 8 more genes related to polygalacturonase/pectinase activity in V. dahliae. Transcripts of PGA increased in the △exopg mutant in response to potato leaf extracts, compared to the wild type. The expression pattern of those eight genes showed similar trends in the △exopg mutant and in the weakly aggressive isolate in response to potato extracts, but without the increase of PGA in the weakly aggressive isolate to leaf extracts. This indicated that the △exopg mutant of V. dahliae compensated by the suppression of ExoPG by activating other related gene.

scholarly journals A Role of Calcium Signaling Genes in Heterokaryon Incompatibility in Neurospora crassa

2015 ◽  
Vol 3 (4) ◽  
pp. 668-679
Author(s):  
Ravi Gedela ◽  
Ranjan Tamuli
Keyword(s):  
Neurospora Crassa ◽  
Mating Type ◽  
Gene Deletion ◽  
Deletion Mutants ◽  
Gene Products ◽  
Wild Type ◽  
Heterokaryon Incompatibility ◽  
Knockout Mutants ◽  
Wild Type Control

We have studied the Ca2+-signaling knockout mutants for their role in mating-type-associated heterokaryon incompatibility in Neurospora crassa.  The found results showed on heterokaryons homokaryosis for DNCU05225, DNCU06366, DNCU06650, DNCU07075, and ∆NCU07966 Ca2+-signaling knockout mutants (Neurospora crassa unit number, NCU) displayed heterokaryon het compatibility; however heterokaryons heterokaryosis for DNCU05225, DNCU063665, DNCU06650, DNCU07075, and ∆NCU07966 mutants displayed het incompatibility like the wild-type control.  In addition to that Two Ca2+-signaling knockout mutants DNCU02283, and DNCU09655 were tested for mating-type-associated heterokaryon incompatibility; these results showed, heterokaryons homokaryosis and heterokaryons heterokaryosis for DNCU02283, DNCU09655 mutants displayed het incompatibility.  Cell death and hyphal compartmentation due to mating type associated incompatibility were confirmed by uptake of vital dye Evan’s blue.  Thus, these results of NCU05225, NCU06366, NCU06650, NCU07075, and NCU07966 Ca2+-signaling gene products could play a role in mating-type-associated heterokaryon incompatibility in N. crassa.  In this article, we are reporting initially screened Ca2+-signaling gene deletion mutants of these five acts as recessive suppressors of mating type associated vegetative incompatibility in N. crassa.Int J Appl Sci Biotechnol, Vol 3(4): 668-679

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