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

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Abstract

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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Acknowledgments

We thank Z. Hampejsova for the experimental work on transgene copy estimation. This work was supported by the Czech Science Foundation (Grant Agreement No. 13-07996S), by BIOCEV CZ.1.05/1.1.00/02.0109 from the ERDF, “Biotechnological expert” CZ.1.07/2.3.00/30.0020 from the European Social Fund and the state budget of the Czech Republic, and by Grant No. AVOZ50520701 from the Czech Ministry of Education, Youth and Sports. 

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The authors declare that they have no competing interests.

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Authors and Affiliations

  1. Institute of Experimental Medicine, CAS, Prague, Czechia

    Tetyana Chumak, Daniela Buckiova & Josef Syka

  2. Laboratory of Molecular Pathogenetics, Institute of Biotechnology, CAS, Prague 4, CZ-142 20, Prague, Czechia

    Romana Bohuslavova, Iva Macova, Nicole Dodd & Gabriela Pavlinkova

  3. Department of Biology, University of Iowa, Iowa City, IA, 52242, USA

    Bernd Fritzsch

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  1. Tetyana Chumak
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  2. Romana Bohuslavova
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Fig. S1

External phenotype of E10.5 embryos. Heterozygous transgenic (Tg +/−) embryos did not show any abnormal gross appearance compared to WT littermates. However, transgenic homozygous embryos (Tg +/+) showed severe abnormalities in the mid-hindbrain region (arrow) and signs of developmental arrest (PDF 514 kb)

Fig. S2

Age-related hearing loss in WT and Tg +/− animals. In WT animals, hearing decline is uniform in all frequencies with a more significant deterioration of hearing at 10–15 months of age (A, C). In contrast, DPOAEs disappear completely and ABR thresholds are significantly elevated in Tg +/− animals in the age of 6–9 months (B, D). Results are means ± SEM for DPOAEs and means ± SD for hearing thresholds. *P < 0.05, **P < 0.01, two-way ANOVA with the Bonferroni correction test (PDF 69 kb)

Fig. S3

Differences in the number of spiral ganglion neurons between WT and TG +/− animals. A significantly lower number of SGNs is found in all cochlear turns in Tg +/− mice compared to WT in all age groups with a slightly larger loss in the basal and middle turn of Tg +/− cochlea at 10–15 months of age. Results are means ± SD, ***P < 0.001, one-way ANOVA with the Bonferroni correction test (PDF 57 kb)

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Chumak, T., Bohuslavova, R., Macova, I. et al. Deterioration of the Medial Olivocochlear Efferent System Accelerates Age-Related Hearing Loss in Pax2-Isl1 Transgenic Mice. Mol Neurobiol 53, 2368–2383 (2016). https://doi.org/10.1007/s12035-015-9215-1

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