Biology subjects

Avraham, K. B.

Publications and source records attributed to Avraham, K. B..

9 recordsLinked to original sources

bioRxiv2025

Multimodal profiling reveals a Notch-responsive regenerative subpopulation of cochlear supporting cells

Regeneration enables organisms to repair damaged tissues, yet this capacity is strikingly limited in the cochlear sensory epithelium, essential for sound detection. A major cause of hearing loss arises from the irreversible loss of sensory hair cells (HCs) in the cochlea. While supporting cells (SCs) have a latent ability to transdifferentiate into HCs, this regenerative potential is rapidly lost after development. Using live imaging and single-cell multi-omics of cochlear explants, we uncovered the cellular and molecular heterogeneity underlying the limited regenerative capacity of the neonatal mouse cochlea. Notch repression broadly silenced key SC genes, yet only a rare subpopulation of Deiters cells (DC), termed transdifferentiating DCs (tDCs), initiated the transdifferentiation into HC fate. These cells underwent coordinated transcriptional and enhancer remodeling, linking epigenetic priming with morphological plasticity, while other SCs remained refractory despite robust Notch targets downregulation. Our study provides a molecular definition of an early induced transitional DC to HC state, revealing Notch inhibition as a selective trigger that unmasks rare regenerative competence.

developmental biology↗

bioRxiv2021

A nesprin-4/kinesin-1 cargo model for nucleus positioning in cochlear outer hair cells

Nuclear positioning is important for the functionality of many cell types and is mediated by interactions of cytoskeletal elements and nucleoskeleton proteins. Nesprin proteins, part of the linker of nucleoskeleton and cytoskeleton (LINC) complex, have been shown to participate in nuclear positioning in multiple cell types. Outer hair cells (OHCs) in the inner ear are specialized sensory epithelial cells that utilize somatic electromotility to amplify auditory signals in the cochlea. Recently, nesprin-4 (encoded by Syne4) was shown to play a crucial role in nuclear positioning in OHCs. Syne4 deficiency in humans and mice leads to mislocalization of the OHC nuclei and cell death resulting in deafness. However, it is unknown how nesprin-4 mediates the position of the nucleus, and which other molecular components are involved in this process. Here, we show that the interaction of nesprin-4 and the microtubule motor kinesin-1 is mediated by a conserved 4 amino-acid motif. Using in-vivo AAV gene delivery, we show that this interaction is critical for nuclear positioning and hearing in mice. Nuclear mislocalization and cell death of OHCs coincide with the onset of hearing and electromotility and are solely restricted to outer, but not inner, hair cells. Likewise, the C. elegans functional homolog of nesprin-4, UNC-83, uses a similar motif to mediate interactions between migrating nuclei and kinesin-1. Overall, our results suggest that OHCs require unique cellular machinery for proper nuclear positioning at the onset of electromotility. This machinery relies on the interaction between nesprin-4 and kinesin-1 motors supporting a microtubule cargo model for nuclear positioning.

cell biology↗

bioRxiv2021

Repair of Noise-Induced Damage to Stereocilia F-actin Cores is Facilitated by XIRP2

Prolonged exposure to loud noise has been shown to affect inner ear sensory hair cells in a variety of deleterious manners, including damaging the stereocilia core. The damaged sites can be visualized as "gaps" in phalloidin staining of F-actin, and the enrichment of monomeric actin at these sites, along with an actin nucleator and crosslinker, suggests that localized remodeling occurs to repair the broken filaments. Herein we show that gaps in mouse auditory hair cells are largely repaired within one week of traumatic noise exposure through the incorporation of newly synthesized actin. Additionally, we report that XIRP2 is required for the repair process and facilitates the enrichment of monomeric{gamma} -actin at gaps through its LIM domain-containing C-terminus. Our study describes a novel process by which hair cells can recover from sub-lethal hair bundle damage and which may contribute to recovery from temporary hearing threshold shifts and the prevention of age-related hearing loss.

neuroscience↗

bioRxiv2021

Genetic and phenotypic heterogeneity in PNPT1, MYO15A, PTPRQ and SLC12A2 variants detected among hearing impaired assortative mating families in Southern India

Exome analysis was used to resolve the etiology of hearing loss (HL) in four South Indian assortative mating families. Six variants, including three novel ones, were identified in four genes: PNPT1 p.Ala46Gly and p.Asn540Ser, MYO15A p.Leu1485Pro and p.Tyr1891*, PTPRQ p.Gln1336*, and SLC12A2 p.Pro988Ser. Compound heterozygous PNPT1 variants were associated with prelingual profound sensorineural hearing loss (SNHL), vestibular dysfunction and unilateral progressive vision loss in one family. In the second family, MYO15A variants in the myosin motor domain, including a novel variant, were found to be associated with prelingual profound SNHL. A novel PTPRQ variant was associated with postlingual progressive sensorineural/mixed HL and vestibular dysfunction in the third family, with mastoid bone hypopneumatization observed in one family member. In the fourth family, the SLC12A2 novel variant was found to segregate with severe-to-profound HL causing DFNA78, across three generations. Our results suggest a high level of allelic, genotypic and phenotypic heterogeneity of HL in these families. This study is the first to report the association of PNPT1, PTPRQ and SLC12A2 variants with HL in the Indian population.

genetics↗

bioRxiv2020

A lesson from COVID-19 on inaccessibility of web-based information for disabled populations worldwide

Many government websites and mobile content are inaccessible for people with vision, hearing, and cognitive disabilities. The COVID-19 pandemic highlighted these disparities when health authority website information, critical in providing resources for curbing the spread of the virus, remained inaccessible for disabled populations. The Web Content Accessibility Guidelines provide comparatively universally accepted guidelines for website accessibility. We utilized these parameters to examine the number of countries with or without accessible health authority websites. The resulting data indicate a dearth of countries with websites accessible for persons with disabilities. Methods of information dissemination must take into consideration individuals with disabilities, particularly in times of global health crises.

scientific communication and education↗

bioRxiv2020

Homozygote loss-of-function variants in the human COCH gene underlie hearing loss

Since 1999, the COCH gene encoding cochlin, has been linked to the autosomal dominant non-syndromic hearing loss, DFNA9, with or without vestibular abnormalities. The hearing impairment associated with the variants affecting gene function has been attributed to a dominant-negative effect. Mutant cochlin was seen to accumulate intracellularly, with the formation of aggregates both inside and outside the cells, in contrast to the wild-type cochlin that is normally secreted. While an additional recessive variant in the COCH gene (DFNB110) has recently been reported, the mechanism of the loss-of-function (LOF) effect of the COCH gene product remains unknown. In this study, we used COS7 cell lines to investigate the consequences of a novel homozygous frameshift variant on RNA transcription, and on cochlin translation. Our results indicate a LOF effect of the variant and a major decrease in cochlin translation. This data has a dramatic impact on the accuracy of genetic counseling for both heterozygote and homozygote carriers of LOF variants in COCH.

genetics↗

bioRxiv2020

Striatin is required for hearing and affects inner hair cells and ribbon synapses

Striatin, a subunit of the serine/threonine phosphatase PP2A, is a core member of the conserved striatin-interacting phosphatase and kinase (STRIPAK) complexes. The protein is expressed in the cell junctions between epithelial cells, which play a role in maintaining cell-cell junctional integrity. Since adhesion is crucial for the function of the mammalian inner ear, we examined the localization and function of striatin in the mouse cochlea. Our results show that in neonatal mice, striatin is specifically expressed in the cell-cell junctions of the inner hair cells, the receptor cells in the mammalian cochlea. Auditory brainstem response measurements of striatin-deficient mice indicated a progressive, high-frequency hearing loss, suggesting that striatin is essential for normal hearing. Moreover, scanning electron micrographs of the organ of Corti revealed a moderate degeneration of the outer hair cells in the middle and basal regions, concordant with the high-frequency hearing loss. Importantly, striatin-deficient mice show aberrant ribbon synapse maturation that may lead to the observed auditory impairment. Together, these results suggest a novel function for striatin in the mammalian auditory system.

cell biology↗

bioRxiv2019

Shear forces drive precise patterning of hair cells in the mammalian inner ear

Precise cellular organizations are required for the function of many organs and tissues. It is often unclear, however, how such precise patterns emerge during development. The mammalian hearing organ, the organ of Corti, consists of a remarkably organized pattern of four rows of hair cells (HCs) interspersed by non-sensory supporting cells (SCs). This checkerboard-like pattern of HCs and SCs emerges from a disordered epithelium over several days, yet the transition to an ordered cellular pattern is not well understood. Using a combination of quantitative morphological analysis and time-lapse imaging of mouse cochlear explants, we show here that patterning of the organ of Corti involves dynamic reorganizations that include lateral shear motion, cell intercalations, and delaminations. A mathematical model, where tissue morphology is described in terms of the mechanical forces that act on cells and cellular junctions, suggests that global shear on HCs and local repulsion between HCs are sufficient to drive the tissue into the final checkerboard-like pattern. Our findings suggest that precise patterns can emerge during development from reorganization processes, driven by a combination of global and local forces in a process analogous to shear-induced crystallization.

developmental biology↗

bioRxiv2018

DNA methylation dynamics during embryonic development and postnatal maturation of the mouse auditory organ of Corti

BackgroundThe mammalian inner ear is a complex morphological structure responsible for hearing and balance, and its pathology is associated with deafness and balance disorders. To evaluate the role of epigenomic dynamics in the development and maturation of mouse inner ear sensory epithelium, we performed whole-genome bisulfite sequencing on inner ear tissue, yielding temporal base-pair resolution methylomes at key developmental time points.\n\nResultsWe found a late accumulation of non-CpG methylation, indicating a similarity between the inner ear sensory epithelium and neuronal tissue. Moreover, annotation of both unmethylated and low methylated regions pointed to regulatory elements active in the inner ear in proximity of and distal from transcriptional units. Finally, we identified differentially methylated regions across the transition periods. An analysis of these regions led us to identify several novel candidate regulatory factors, connecting regulatory elements from specific time points in development to molecular features that drive the development and maturation of the inner ear sensory epithelium. The GJB6 locus putative regulatory region was shown to upregulate distal GJB6 gene expression and a non-coding RNA.\n\nConclusionsOur analysis of inner ear sensory epithelium DNA methylation sheds light on novel regulatory regions in the hearing organ, and may help boost diagnostic capabilities and guide the development of therapeutics for hearing loss, by providing multiple intervention points for manipulation of the auditory system.

genomics↗