Deletion of Kncn Does Not Affect Kinocilium and Stereocilia Bundle Morphogenesis and Mechanotransduction in Cochlear Hair Cells

Hu, Qun; Li, Guo; Li, Jie; Song, Chi Young; Yu, Lisheng; He, David Z.Z.; Xiong, Wei

doi:10.3389/fnmol.2018.00326

Cited by 5 publications

(4 citation statements)

References 27 publications

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“…Moreover, we observed a profound alteration of the kinocilium length and a disarray of the whole stereociliary bundle. As the microtubule-based kinocilium dictates the correct development of the bundle [ 27 , 28 ], we hypothesized that an Smpx deficiency might negatively influence the structure of the kinocilium, thus altering the conformation of the nascent stereociliary bundle. Additionally, as Smpx is localized in the actin-rich CP of the hair cells [ 4 ] and participates in the regulation of the dynamics of the cytoskeleton [ 7 ], it would be also conceivable that the absence of Smpx might disorganize the actin cytoskeleton of the stereocilia, thus causing the disarray of the sensory bundle.…”

Section: Discussionmentioning

confidence: 99%

“…In this study, we employ zebrafish to mimic the lack of functional SMPX, representative of the condition in the inner ear hair cells of patients, through the downregulation of smpx by means of two gene-specific Morpholino antisense oligomers. Using the Smpx-deficient larvae, we show that Smpx plays a critical role in the organization of the sensory bundle of hair cells: a low level of Smpx is associated with aberrant stereocilia and a profound alteration of the kinocilium; the latter is involved in the morphogenesis of the hair bundle itself [ 27 , 28 ]. Finally, we demonstrate that smpx downregulation hampers the capability of hair cells to perform mechanotransduction.…”

Section: Introductionmentioning

confidence: 99%

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

Ghilardi

Diana

Bacchetta

et al. 2021

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Ghilardi

Diana

Bacchetta

et al. 2021

IJMS

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“…In addition, there were large numbers of abnormal microvilli on HCs and SCs in the cochleae of Dyx1c1 −/− mice ( Figure 4 A,B ). According to previous reports, the kinocilium degenerates prior to the activation of hearing in mice, [ 42 ] and we used SEM to observe the structure of the kinocilium at P4. The distal ends of the kinocilia in the cochleae of Dyx1c1 −/− mice were enlarged and presented as spheroids compared with the WT mice (Figure 4C ).…”

Section: Resultsmentioning

confidence: 99%

Dyslexia‐Related Hearing Loss Occurs Mainly through the Abnormal Spontaneous Electrical Activity of Spiral Ganglion Neurons

Hong

Chen

et al. 2023

Advanced Science

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Dyslexia is a reading and spelling disorder due to neurodevelopmental abnormalities and is occasionally found to be accompanied by hearing loss, but the reason for the associated deafness remains unclear. This study finds that knockout of the dyslexia susceptibility 1 candidate 1 gene (Dyx1c1−/−) in mice, the best gene for studying dyslexia, causes severe hearing loss, and thus it is a good model for studying the mechanism of dyslexia‐related hearing loss (DRHL). This work finds that the Dyx1c1 gene is highly expressed in the mouse cochlea and that the spontaneous electrical activity of inner hair cells and type I spiral ganglion neurons is altered in the cochleae of Dyx1c1−/− mice. In addition, primary ciliary dyskinesia‐related phenotypes such as situs inversus and disrupted ciliary structure are seen in Dyx1c1−/− mice. In conclusion, this study gives new insights into the mechanism of DRHL in detail and suggests that Dyx1c1 may serve as a potential target for the clinical diagnosis of DRHL.

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“…Auditory hair cells (HCs) are mechanoreceptors of the auditory system and each HC has an apically located hair bundle made up of a single kinocilium and many stereocilia ( 11 ). Hearing loss (HL) in relation to HCs’ ciliary defects is also considered to be a kind of ciliopathy ( 12 ).…”

Section: Introductionmentioning

confidence: 99%

Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling

Shi¹,

Wang²,

Zhang³

et al. 2022

JCI Insight

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Defective primary cilia cause a range of diseases called ciliopathies, which include hearing loss (HL). Variants in human oxysterol binding protein like 2 (OSBPL2/ORP2) are responsible for autosomal dominant nonsyndromic HL (DFNA67). However, the pathogenesis of OSBPL2 deficiency has not been fully elucidated. In this study, we showed that the Osbpl2-knockout (KO) mice exhibited progressive HL and abnormal cochlea development with defective cilia. Further research revealed that OSBPL2 was located at the base of kinocilia in hair cells (HCs) and primary cilia in supporting cells (SCs), and functioned in the maintenance of ciliogenesis by regulating the homeostasis of PI(4,5)P2 on the cilia membrane. OSBPL2 deficiency led to a significant increase of PI(4,5)P2 on the cilia membrane, which could be partially rescued by the overexpression of INPP5E. In addition, the key molecules in Sonic Hedgehog (Shh) signaling pathway (SMO and GLI3) were detected to be down-regulated in Osbpl2-KO HEI-OC1 cells. Our findings revealed that OSBPL2 deficiency resulted in ciliary defects and abnormal Shh signaling transduction in auditory cells, which helped to elucidate the underlying mechanism of OSBPL2 deficiency in HL.

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Deletion of Kncn Does Not Affect Kinocilium and Stereocilia Bundle Morphogenesis and Mechanotransduction in Cochlear Hair Cells

Cited by 5 publications

References 27 publications

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

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

Dyslexia‐Related Hearing Loss Occurs Mainly through the Abnormal Spontaneous Electrical Activity of Spiral Ganglion Neurons

Mutations in OSBPL2 cause hearing loss associated with primary cilia defects via sonic hedgehog signaling

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