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Abnormal Innervation, Demyelination, and Degeneration of Spiral Ganglion Neurons as Well as Disruption of Heminodes are Involved in the Onset of Deafness in Cx26 Null Mice

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Abstract

GJB2 gene mutations are the most common causes of autosomal recessive non-syndromic hereditary deafness. For individuals suffering from severe to profound GJB2-related deafness, cochlear implants have emerged as the sole remedy for auditory improvement. Some previous studies have highlighted the crucial role of preserving cochlear neural components in achieving favorable outcomes after cochlear implantation. Thus, we generated a conditional knockout mouse model (Cx26-CKO) in which Cx26 was completely deleted in the cochlear supporting cells driven by the Sox2 promoter. The Cx26-CKO mice showed severe hearing loss and massive loss of hair cells and Deiter’s cells, which represented the extreme form of human deafness caused by GJB2 gene mutations. In addition, multiple pathological changes in the peripheral auditory nervous system were found, including abnormal innervation, demyelination, and degeneration of spiral ganglion neurons as well as disruption of heminodes in Cx26-CKO mice. These findings provide invaluable insights into the deafness mechanism and the treatment for severe deafness in Cx26-null mice.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Qiu Y, Zheng J, Chen S, Sun Y. Connexin mutations and hereditary diseases. Int J Mol Sci 2022, 23: 4255.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hosoya M, Fujioka M, Murayama AY, Ogawa K, Okano H, Ozawa H. Dynamic spatiotemporal expression changes in connexins of the developing primate’s cochlea. Genes (Basel) 2021, 12: 1082.

    Article  CAS  PubMed  Google Scholar 

  3. Lautermann J, ten Cate WJF, Altenhoff P, Grümmer R, Traub O, Frank HG. Expression of the gap-junction connexins 26 and 30 in the rat cochlea. Cell Tissue Res 1998, 294: 415–420.

    Article  CAS  PubMed  Google Scholar 

  4. Liu W, Li H, Edin F, Brännström J, Glueckert R, Schrott-Fischer A, et al. Molecular composition and distribution of gap junctions in the sensory epithelium of the human cochlea-a super-resolution structured illumination microscopy (SR-SIM) study. Ups J Med Sci 2017, 122: 160–170.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Liu W, Edin F, Blom H, Magnusson P, Schrott-Fischer A, Glueckert R, et al. Super-resolution structured illumination fluorescence microscopy of the lateral wall of the cochlea: the Connexin26/30 proteins are separately expressed in man. Cell Tissue Res 2016, 365: 13–27.

    Article  CAS  PubMed  Google Scholar 

  6. Kenna MA, Feldman HA, Neault MW, Frangulov A, Wu BL, Fligor B, et al. Audiologic phenotype and progression in GJB2 (Connexin 26) hearing loss. Arch Otolaryngol Head Neck Surg 2010, 136: 81–87.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Shearer AE, Hildebrand MS, Smith RJ. Hereditary hearing loss and deafness overview. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJ, Stephens K, editors. Gene Review. Seattle (WA): University of Washington; 1993–2018.

  8. Takada Y, Beyer LA, Swiderski DL, O’Neal AL, Prieskorn DM, Shivatzki S, et al. Connexin 26 null mice exhibit spiral ganglion degeneration that can be blocked by BDNF gene therapy. Hear Res 2014, 309: 124–135.

    Article  CAS  PubMed  Google Scholar 

  9. Shearer AE, Eppsteiner RW, Frees K, Tejani V, Sloan-Heggen CM, Brown C, et al. Genetic variants in the peripheral auditory system significantly affect adult cochlear implant performance. Hear Res 2017, 348: 138–142.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Wu CM, Ko HC, Tsou YT, Lin YH, Lin JL, Chen CK, et al. Long-term cochlear implant outcomes in children with GJB2 and SLC26A4 mutations. PLoS One 2015, 10: e0138575.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Barclay M, Ryan AF, Housley GD. Type I vs type II spiral ganglion neurons exhibit differential survival and neuritogenesis during cochlear development. Neural Dev 2011, 6: 33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Huang LC, Thorne PR, Housley GD, Montgomery JM. Spatiotemporal definition of neurite outgrowth, refinement and retraction in the developing mouse cochlea. Development 2007, 134: 2925–2933.

    Article  CAS  PubMed  Google Scholar 

  13. Rubel EW, Fritzsch B. Auditory system development: Primary auditory neurons and their targets. Annu Rev Neurosci 2002, 25: 51–101.

    Article  CAS  PubMed  Google Scholar 

  14. Panganiban CH, Barth JL, Darbelli L, Xing Y, Zhang J, Li H, et al. Noise-induced dysregulation of Quaking RNA binding proteins contributes to auditory nerve demyelination and hearing loss. J Neurosci 2018, 38: 2551–2568.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wan G, Corfas G. Transient auditory nerve demyelination as a new mechanism for hidden hearing loss. Nat Commun 2017, 8: 14487.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  16. Qing Chang. Timed conditional null of connexin26 in mice reveals temporary requirements of connexin26 in key cochlear developmental events before the onset of hearing. Neurobiol Dis 2015, 73: 418–427.

    Article  Google Scholar 

  17. Chen S, Sun Y, Lin X, Kong W. Down regulated connexin26 at different postnatal stage displayed different types of cellular degeneration and formation of organ of Corti. Biochem Biophys Res Commun 2014, 445: 71–77.

    Article  CAS  PubMed  Google Scholar 

  18. Kudo T, Kure S, Ikeda K, Xia AP, Katori Y, Suzuki M, et al. Transgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness. Hum Mol Genet 2003, 12: 995–1004.

    Article  CAS  PubMed  Google Scholar 

  19. Chen S, Xie L, Xu K, Cao HY, Wu X, Xu XX, et al. Developmental abnormalities in supporting cell phalangeal processes and cytoskeleton in the Gjb2 knockdown mouse model. Dis Model Mech 2018, 11: dmm033019.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Liu XZ, Jin Y, Chen S, Xu K, Xie L, Qiu Y, et al. F-actin dysplasia involved in organ of corti deformity in Gjb2 knockdown mouse model. Front Mol Neurosci 2021, 14: 808553.

    Article  CAS  PubMed  Google Scholar 

  21. Amor V, Feinberg K, Eshed-Eisenbach Y, Vainshtein A, Frechter S, Grumet M, et al. Long-term maintenance of Na+ channels at nodes of Ranvier depends on glial contact mediated by gliomedin and NrCAM. J Neurosci 2014, 34: 5089–5098.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chen P, Wu W, Zhang J, Chen J, Li Y, Sun L, et al. Pathological mechanisms of connexin26-related hearing loss: Potassium recycling, ATP-calcium signaling, or energy supply? Front Mol Neurosci 2022, 15: 976388.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Walters BJ, Yamashita T, Zuo J. Sox2-CreER mice are useful for fate mapping of mature, but not neonatal, cochlear supporting cells in hair cell regeneration studies. Sci Rep 2015, 5: 11621.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhu Y, Liang C, Chen J, Zong L, Chen GD, Zhao HB. Active cochlear amplification is dependent on supporting cell gap junctions. Nat Commun 2013, 4: 1786.

    Article  ADS  PubMed  Google Scholar 

  25. Froud KE, Wong AC, Cederholm JM, Klugmann M, Sandow SL, Julien JP, et al. Type II spiral ganglion afferent neurons drive medial olivocochlear reflex suppression of the cochlear amplifier. Nat Commun 2015, 6: 7115.

    Article  ADS  CAS  PubMed  Google Scholar 

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Acknowledgments

We are grateful to the Center for Instrumental Analysis and Metrology, the Institute of Virology, and the Chinese Academy of Science, for the electron microscopy (EM), and thank An-Na Du and Ding Gao for their help with the EM experiments. This work was supported by the National Key Research and Development Program of China (2021YFF0702303) and the National Natural Science Foundation of China (82301324, 82301323, and 82071058).

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Author notes

  1. Yue Qiu and Le Xie contributed equally to this work.

Authors and Affiliations

  1. Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China

    Yue Qiu, Le Xie, Xiaohui Wang, Sen Chen & Yu Sun

  2. Department of Otolaryngology, Nanchang University, Nanchang, 330006, China

    Kai Xu & Xue Bai

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  1. Yue Qiu
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  2. Le Xie
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  3. Xiaohui Wang
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  6. Sen Chen
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  7. Yu Sun
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Correspondence to Sen Chen or Yu Sun.

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Qiu, Y., Xie, L., Wang, X. et al. Abnormal Innervation, Demyelination, and Degeneration of Spiral Ganglion Neurons as Well as Disruption of Heminodes are Involved in the Onset of Deafness in Cx26 Null Mice. Neurosci. Bull. (2024). https://doi.org/10.1007/s12264-023-01167-x

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