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

The mammalian cochlear epithelium undergoes substantial remodeling and maturation before the onset of hearing. However, very little is known about the transcriptional network governing cochlear late-stage maturation and particularly the differentiation of its lateral nonsensory region. Here, we establish ZBTB20 as an essential transcription factor required for cochlear terminal differentiation and maturation and hearing. ZBTB20 is abundantly expressed in the developing and mature cochlear nonsensory epithelial cells, with transient expression in immature hair cells and spiral ganglion neurons. Otocyst-specific deletion of Zbtb20 causes profound deafness with reduced endolymph potential in mice. The subtypes of cochlear epithelial cells are normally generated, but their postnatal development is arrested in the absence of ZBTB20, as manifested by an immature appearance of the organ of Corti, malformation of tectorial membrane (TM), a flattened spiral prominence (SP), and a lack of identifiable Boettcher cells. Furthermore, these defects are related with a failure in the terminal differentiation of the nonsensory epithelium covering the outer border Claudius cells, outer sulcus root cells, and SP epithelial cells. Transcriptome analysis shows that ZBTB20 regulates genes encoding for TM proteins in the greater epithelial ridge, and those preferentially expressed in root cells and SP epithelium. Our results point to ZBTB20 as an essential regulator for postnatal cochlear maturation and particularly for the terminal differentiation of cochlear lateral nonsensory domain.

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“…ABR tests were performed according to a previously reported method ( 69 ) with a detailed protocol described in SI Appendix , Extended Methods .…”

Section: Methodsmentioning

confidence: 99%

ZBTB20 is essential for cochlear maturation and hearing in mice

Xie

Ma²,

Bai

et al. 2023

Proc. Natl. Acad. Sci. U.S.A.

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“…In the central nervous system, there is a developmentally regulated expression of sodium channel genes specifically targeting excitatory or inhibitory neurons which is likely to establish distinct firing rates ( Du et al, 2020 ). In addition to the essential role in action potential discharge, Na + channel expression during development has a role in synaptogenesis ( Chabbert et al, 2003 ; Brugeaud et al, 2007 ; Zu et al, 2021 ) and may be important for cell differentiation and afferentation ( Oliver et al, 1997 ; Wooltorton et al, 2007 ).…”

Section: Introductionmentioning

confidence: 99%

Expression and Physiology of Voltage-Gated Sodium Channels in Developing Human Inner Ear

et al. 2021

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Sodium channel expression in inner ear afferents is essential for the transmission of vestibular and auditory information to the central nervous system. During development, however, there is also a transient expression of Na+ channels in vestibular and auditory hair cells. Using qPCR analysis, we describe the expression of four Na+ channel genes, SCN5A (Nav1.5), SCN8A (Nav1.6), SCN9A (Nav1.7), and SCN10A (Nav1.8) in the human fetal cristae ampullares, utricle, and base, middle, and apex of the cochlea. Our data show distinct patterns of Na+ channel gene expression with age and between these inner ear organs. In the utricle, there was a general trend toward fold-change increases in expression of SCN8A, SCN9A, and SCN10A with age, while the crista exhibited fold-change increases in SCN5A and SCN8A and fold-change decreases in SCN9A and SCN10A. Fold-change differences of each gene in the cochlea were more complex and likely related to distinct patterns of expression based on tonotopy. Generally, the relative expression of SCN genes in the cochlea was greater than that in utricle and cristae ampullares. We also recorded Na+ currents from developing human vestibular hair cells aged 10–11 weeks gestation (WG), 12–13 WG, and 14+ WG and found there is a decrease in the number of vestibular hair cells that exhibit Na+ currents with increasing gestational age. Na+ current properties and responses to the application of tetrodotoxin (TTX; 1 μM) in human fetal vestibular hair cells are consistent with those recorded in other species during embryonic and postnatal development. Both TTX-sensitive and TTX-resistant currents are present in human fetal vestibular hair cells. These results provide a timeline of sodium channel gene expression in inner ear neuroepithelium and the physiological characterization of Na+ currents in human fetal vestibular neuroepithelium. Understanding the normal developmental timeline of ion channel gene expression and when cells express functional ion channels is essential information for regenerative technologies.

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Pathological changes of the sural nerve in patients with familial episodic pain syndrome

Zheng

Huang

et al. 2022

Neurol Sci

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

Cited by 4 publications

References 46 publications

ZBTB20 is essential for cochlear maturation and hearing in mice

ZBTB20 is essential for cochlear maturation and hearing in mice

Expression and Physiology of Voltage-Gated Sodium Channels in Developing Human Inner Ear

Pathological changes of the sural nerve in patients with familial episodic pain syndrome

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