Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through Kv7.4 channel upsurge in auditory neurons and hair cells
- Hebei Medical University, China
- University of Oxford, United Kingdom
- University of Leeds, United Kingdom
- University of Nevada Reno, United States
Abstract
Repressor element 1-silencing transcription factor (REST) is a transcriptional repressor that recognizes neuron-restrictive silencer elements in the mammalian genomes in a tissue- and cell-specific manner. The identity of REST target genes and molecular details of how REST regulates them are emerging. We performed conditional null deletion of Rest (cKO), mainly restricted to murine hair cells (HCs) and auditory neurons (aka spiral ganglion neurons (SGNs)). Null-inactivation of full-length REST did not affect the development of normal HCs and SGNs but manifested as progressive hearing loss in adult mice. We found that the inactivation of REST resulted in an increased abundance of Kv7.4 channels at the transcript, protein, and functional levels. Specifically, we found that SGNs and HCs from Rest cKO mice displayed increased Kv7.4 expression and augmented Kv7 currents; SGN’s excitability was also significantly reduced. Administration of a compound with Kv7.4 channel activator activity, fasudil, recapitulated progressive hearing loss in mice. In contrast, inhibition of the Kv7 channels by XE991 rescued the auditory phenotype of Rest cKO mice. Previous studies identified some loss-of-function mutations within the Kv7.4-coding gene, Kcnq4, as a causative factor for progressive hearing loss in mice and humans. Thus, the findings reveal that a critical homeostatic Kv7.4 channel level is required for proper auditory functions.
Data availability
All data generated or analyzed are included in the source data
Article and author information
Author details
Funding
National Institute on Deafness and Other Communication Disorders (DC015135,DC016099)
- Ebenezer N Yamoah
National Institute on Aging (AG060504-01,P01 AG051443)
- Ebenezer N Yamoah
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All experimental animal protocols were performed following the Animal Care and Ethical Committee of Hebei Medical University (Shijiazhuang, China). 01644
Copyright
© 2022, Zhang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 809
- views
-
- 226
- downloads
-
- 0
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Repressor element 1-silencing transcription factor deficiency yields profound hearing loss through Kv7.4 channel upsurge in auditory neurons and hair cells
eLife 11:e76754.
https://doi.org/10.7554/eLife.76754
Further reading
-
- Medicine
- Neuroscience
Monomethyl fumarate (MMF) and its prodrug dimethyl fumarate (DMF) are currently the most widely used agents for the treatment of multiple sclerosis (MS). However, not all patients benefit from DMF. We hypothesized that the variable response of patients may be due to their diet. In support of this hypothesis, mice subjected to experimental autoimmune encephalomyelitis (EAE), a model of MS, did not benefit from DMF treatment when fed a lauric acid-rich (LA) diet. Mice on normal chow (NC) diet, in contrast, and even more so mice on high-fiber (HFb) diet showed the expected protective DMF effect. DMF lacked efficacy in the LA diet-fed group despite similar resorption and preserved effects on plasma lipids. When mice were fed the permissive HFb diet, the protective effect of DMF treatment depended on hydroxycarboxylic receptor 2 (HCAR2) which is highly expressed in neutrophil granulocytes. Indeed, deletion of Hcar2 in neutrophils abrogated DMF protective effects in EAE. Diet had a profound effect on the transcriptional profile of neutrophils and modulated their response to MMF. In summary, DMF required HCAR2 on neutrophils as well as permissive dietary effects for its therapeutic action. Translating the dietary intervention into the clinic may improve MS therapy.
-
- Medicine
Inherited retinal degenerations (IRDs) constitute a group of clinically and genetically diverse vision-impairing disorders. Retinitis pigmentosa (RP), the most common form of IRD, is characterized by gradual dysfunction and degeneration of rod photoreceptors, followed by the loss of cone photoreceptors. Recently, we identified reserpine as a lead molecule for maintaining rod survival in mouse and human retinal organoids as well as in the rd16 mouse, which phenocopy Leber congenital amaurosis caused by mutations in the cilia-centrosomal gene CEP290 (Chen et al., 2023). Here, we show the therapeutic potential of reserpine in a rhodopsin P23H rat model of autosomal dominant RP. At postnatal day (P) 68, when males and females are analyzed together, the reserpine-treated rats exhibit higher rod-derived scotopic b-wave amplitudes compared to the controls with little or no change in scotopic a-wave or cone-derived photopic b-wave. Interestingly, the reserpine-treated female rats display enhanced scotopic a- and b-waves and photopic b-wave responses at P68, along with a better contrast threshold and increased outer nuclear layer thickness. The female rats demonstrate better preservation of both rod and cone photoreceptors following reserpine treatment. Retinal transcriptome analysis reveals sex-specific responses to reserpine, with significant upregulation of phototransduction genes and proteostasis-related pathways, and notably, genes associated with stress response. This study builds upon our previously reported results reaffirming the potential of reserpine for gene-agnostic treatment of IRDs and emphasizes the importance of biological sex in retinal disease research and therapy development.
