Selective Ablation of Pillar and Deiters' Cells Severely Affects Cochlear Postnatal Development and Hearing in Mice

Lagarde, Marcia M. Mellado; Cox, Brandon C.; Fang, Jie; Taylor, Ruth; Forge, Andrew; Zuo, Jian

doi:10.1523/jneurosci.3088-12.2013

Cited by 53 publications

(43 citation statements)

References 84 publications

(116 reference statements)

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“…However, HCs, including the newly regenerated HCs, will also undergo cell death in absence of SCs [10, 16]. In this study, the number of HCs in the cochleae from the DMSO-DAPT group was also significantly increased accompanied by a sharp decrease in SC number.…”

Section: Discussionmentioning

confidence: 67%

Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

Zeng

et al. 2016

Oncotarget

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Hair cell (HC) loss is the main cause of permanent hearing loss in mammals. Previous studies have reported that in neonatal mice cochleae, Wnt activation promotes supporting cell (SC) proliferation and Notch inhibition promotes the trans-differentiation of SCs into HCs. However, Wnt activation alone fails to regenerate significant amounts of new HCs, Notch inhibition alone regenerates the HCs at the cost of exhausting the SC population, which leads to the death of the newly regenerated HCs. Mitotic HC regeneration might preserve the SC number while regenerating the HCs, which could be a better approach for long-term HC regeneration. We present a two-step gene manipulation, Wnt activation followed by Notch inhibition, to accomplish mitotic regeneration of HCs while partially preserving the SC number. We show that Wnt activation followed by Notch inhibition strongly promotes the mitotic regeneration of new HCs in both normal and neomycin-damaged cochleae while partially preserving the SC number. Lineage tracing shows that the majority of the mitotically regenerated HCs are derived specifically from the Lgr5+ progenitors with or without HC damage. Our findings suggest that the co-regulation of Wnt and Notch signaling might provide a better approach to mitotically regenerate HCs from Lgr5+ progenitor cells.

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Section: Discussionmentioning

confidence: 67%

Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

Zeng

et al. 2016

Oncotarget

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“…For example, the deletion of connexin 26 in DCs and outer pillar cells reduces cochlear amplification and DPOAEs [69] or Vangl2 conditional knockout mice changes the shape and distribution of outer pillar cell and DC phalangeal processes with the reduction in otoacoustic emissions [41]. The ablation of the pillar cells and DCs negatively affects OHCs [70]. Although we have not detected any loss of DCs (nuclear staining) in Tg +/− animals, the loss of ChAT + swellings of vesiculated efferent fibers in Tg +/− animals may affect DC function and, consequently, the function of OHCs.…”

Section: Discussionmentioning

confidence: 99%

Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice

et al. 2015

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The development, maturation, and maintenance of the inner ear are governed by temporal and spatial expression cascades of transcription factors that form a gene regulatory network. ISLET1 (ISL1) may be one of the major players in this cascade, and in order to study its role in the regulation of inner ear development, we produced a transgenic mouse overexpressing Isl1 under the Pax2 promoter. Pax2-regulated ISL1 overexpression increases the embryonic ISL1(+) domain and induces accelerated nerve fiber extension and branching in E12.5 embryos. Despite these gains in early development, the overexpression of ISL1 impairs the maintenance and function of hair cells of the organ of Corti. Mutant mice exhibit hyperactivity, circling behavior, and progressive age-related decline in hearing functions, which is reflected in reduced otoacoustic emissions (DPOAEs) followed by elevated hearing thresholds. The reduction of the amplitude of DPOAEs in transgenic mice was first detected at 1 month of age. By 6-9 months of age, DPOAEs completely disappeared, suggesting a functional inefficiency of outer hair cells (OHCs). The timing of DPOAE reduction coincides with the onset of the deterioration of cochlear efferent terminals. In contrast to these effects on efferents, we only found a moderate loss of OHCs and spiral ganglion neurons. For the first time, our results show that the genetic alteration of the medial olivocochlear (MOC) efferent system induces an early onset of age-related hearing loss. Thus, the neurodegeneration of the MOC system could be a contributing factor to the pathology of age-related hearing loss.

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“…These stimuli have only little effect on cell cycle activity of adult SCs. Although hair cell re-growth might be achieved through SC-to-hair-cell transdifferentiation, SC depletion at the expense of new hair cells may not be a viable therapeutic approach [32]. Unscheduled cell cycle re-entry and DNA damage have been linked to neurodegenerative diseases [33] and to restrictions in stem cell reprogramming [2].…”

Section: Discussionmentioning

confidence: 99%

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

Laos

Anttonen

Kirjavainen

et al. 2014

Aging

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Supporting cells (SCs) of the cochlear (auditory) and vestibular (balance) organs hold promise as a platform for therapeutic regeneration of the sensory hair cells. Prior data have shown proliferative restrictions of adult SCs forced to re-enter the cell cycle. By comparing juvenile and adult SCs in explant cultures, we have here studied how proliferative restrictions are linked with DNA damage signaling. Cyclin D1 overexpression, used to stimulate cell cycle re-entry, triggered higher proliferative activity of juvenile SCs. Phosphorylated form of histone H2AX (γH2AX) and p53 binding protein 1 (53BP1) were induced in a foci-like pattern in SCs of both ages as an indication of DNA double-strand break formation and activated DNA damage response. Compared to juvenile SCs, γH2AX and the repair protein Rad51 were resolved with slower kinetics in adult SCs, accompanied by increased apoptosis. Consistent with the in vitro data, in a Rb mutant mouse model in vivo, cell cycle re-entry of SCs was associated with γH2AX foci induction. In contrast to cell cycle reactivation, pharmacological stimulation of SC-to-hair-cell transdifferentiation in vitro did not trigger γH2AX. Thus, DNA damage and its prolonged resolution are critical barriers in the efforts to stimulate proliferation of the adult inner ear SCs.

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Selective Ablation of Pillar and Deiters' Cells Severely Affects Cochlear Postnatal Development and Hearing in Mice

Cited by 53 publications

References 84 publications

Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

Wnt activation followed by Notch inhibition promotes mitotic hair cell regeneration in the postnatal mouse cochlea

Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice

DNA damage signaling regulates age-dependent proliferative capacity of quiescent inner ear supporting cells

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