Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

Takada, Yuji; Beyer, Lisa A.; Swiderski, Donald L.; O'Neal, Aubrey L.; Prieskorn, Diane M.; Shivatzki, Shaked; Avraham, Karen B.; Raphael, Yehoash

doi:10.1016/j.heares.2013.11.009

Cited by 49 publications

(35 citation statements)

References 68 publications

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“…The severe cochlear pathology and hearing deficits in the Gjb2 -CKO mouse studied here have been previously documented (Takada et al, 2014). Other mouse models with Cx26 mutations have also revealed severe cochlear dysfunction and pathologies (Cohen-Salmon et al, 2002; Kudo et al, 2003; Sun et al, 2009).…”

Section: Discussionsupporting

confidence: 53%

Mice with conditional deletion of Cx26 exhibit no vestibular phenotype despite secondary loss of Cx30 in the vestibular end organs

Lee

Takada

et al. 2015

Hearing Research

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Connexins are components of gap junctions which facilitate transfer of small molecules between cells. One member of the connexin family, Connexin 26 (Cx26), is prevalent in gap junctions in sensory epithelia of the inner ear. Mutations of GJB2, the gene encoding Cx26, cause significant hearing loss in humans. The vestibular system, however, does not usually show significant functional deficits in humans with this mutation. Mouse models for loss of Cx26 function demonstrate hearing loss and cochlear pathology but the extent of vestibular dysfunction and organ pathology are less well characterized. To understand the vestibular effects of Cx26 mutations, we evaluated vestibular function and histology of the vestibular sensory epithelia in a conditional knockout (CKO) mouse with Cx26 loss of function. Transgenic C57BL/6 mice, in which cre-Sox10 drives excision of the Cx26 gene from non-sensory cells flanking the sensory epithelium of the inner ear (Gjb2-CKO), were compared to age-matched wild types. Animals were sacrificed at ages between 4 and 40 weeks and their cochlear and vestibular sensory organs harvested for histological examination. Cx26 immunoreactivity was prominent in the peripheral vestibular system and the cochlea of wild type mice, but absent in the Gjb2-CKO specimens. The hair cell population in the cochleae of the Gjb2-CKO mice was severely depleted but in the vestibular organs it was intact, despite absence of Cx26 expression. The vestibular organs appeared normal at the latest time point examined, 40 weeks. To determine whether compensation by another connexin explains survival of the normal vestibular sensory epithelium, we evaluated the presence of Cx30 in the Gjb2-CKO mouse. We found that Cx30 labeling was normal in the cochlea, but it was decreased or absent in the vestibular system. The vestibular phenotype of the mutants was not different from wild-types as determined by time on the rotarod, head stability tests and physiological responses to vestibular stimulation. Thus presence of Cx30 in the cochlea does not compensate for Cx26 loss, and the absence of both connexins from vestibular sensory epithelia is no more injurious than the absence of one of them. Further studies to uncover the physiological foundation for this difference between the cochlea and the vestibular organs may help in designing treatments for GJB2 mutations.

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Section: Discussionsupporting

confidence: 53%

Mice with conditional deletion of Cx26 exhibit no vestibular phenotype despite secondary loss of Cx30 in the vestibular end organs

Lee

Takada

et al. 2015

Hearing Research

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“…In accordance with this possibility, mutations in the connexin 26 (Cx26) gene (GJB2 mutations), which forms gap junctions between SCs (48, 49), causes deafness. Mice with Cx26 loss show HC loss only after the onset of hearing (50,51), providing evidence that SCs are key regulators of homeostasis during sensory processing in the functional organ of Corti. We also found that HCs must be present in the neonatal organ of Corti for IBC/ IPhC replacement to occur after ablation.…”

Section: Discussionmentioning

confidence: 98%

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Lagarde

Wan

Zhang

et al. 2014

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

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Supporting cells in the cochlea play critical roles in the development, maintenance, and function of sensory hair cells and auditory neurons. Although the loss of hair cells or auditory neurons results in sensorineural hearing loss, the consequence of supporting cell loss on auditory function is largely unknown. In this study, we specifically ablated inner border cells (IBCs) and inner phalangeal cells (IPhCs), the two types of supporting cells surrounding inner hair cells (IHCs) in mice in vivo. We demonstrate that the organ of Corti has the intrinsic capacity to replenish IBCs/IPhCs effectively during early postnatal development. Repopulation depends on the presence of hair cells and cells within the greater epithelial ridge and is independent of cell proliferation. This plastic response in the neonatal cochlea preserves neuronal survival, afferent innervation, and hearing sensitivity in adult mice. In contrast, the capacity for IBC/IPhC regeneration is lost in the mature organ of Corti, and consequently IHC survival and hearing sensitivity are impaired significantly, demonstrating that there is a critical period for the regeneration of cochlear supporting cells. Our findings indicate that the quiescent neonatal organ of Corti can replenish specific supporting cells completely after loss in vivo to guarantee mature hearing function.deafness | cell ablation | hair cell | organ of Corti | glia

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“…We determined the thresholds in the left ear of each animal with auditory brainstem response (ABR) measurements, as described in detail previously (Takada et al, 2014). ABRs were measured at 8, 20, and 32 kHz at least 1 day prior to DT injection or noise exposure (baseline ABRs) and then again 1 month later (N = 5 WT and DT 1M, and N = 9 for Noise group).…”

Section: Methodsmentioning

confidence: 99%

Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus

et al. 2016

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In experimental animal models of auditory hair cell (HC) loss, insults such as noise or ototoxic drugs often lead to secondary changes or degeneration in non-sensory cells and neural components, including reduced density of spiral ganglion neurons, demyelination of auditory nerve fibers and altered cell numbers and innervation patterns in the cochlear nucleus. However, it is not clear whether loss of HCs alone leads to secondary degeneration in these neural components of the auditory pathway. To elucidate this issue, we investigated changes of central components after cochlear insults specific to HCs using diphtheria toxin receptor (DTR) mice expressing DTR only in HCs and exhibiting complete HC loss when injected with diphtheria toxin (DT). We showed that DT-induced HC ablation has no significant impacts on the survival of auditory neurons, central synaptic terminals, and myelin, despite complete HC loss and profound deafness. In contrast, noise exposure induced significant changes in synapses, myelin and CN organization even without loss of inner HCs. We observed a decrease of neuronal size in the auditory pathway, including peripheral axons, spiral ganglion neurons, and cochlear nucleus neurons, likely due to loss of input from the cochlea. Taken together, selective HC ablation and noise exposure showed different patterns of pathology in the auditory pathway and the presence of HCs is not essential for the maintenance of central synaptic connectivity and myelination.

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Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy

Cited by 49 publications

References 68 publications

Mice with conditional deletion of Cx26 exhibit no vestibular phenotype despite secondary loss of Cx30 in the vestibular end organs

Mice with conditional deletion of Cx26 exhibit no vestibular phenotype despite secondary loss of Cx30 in the vestibular end organs

Spontaneous regeneration of cochlear supporting cells after neonatal ablation ensures hearing in the adult mouse

Selective hair cell ablation and noise exposure lead to different patterns of changes in the cochlea and the cochlear nucleus

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