Advertisement

Molecular Neurobiology

, Volume 55, Issue 8, pp 6518–6532 | Cite as

Exocyst Complex Member EXOC5 Is Required for Survival of Hair Cells and Spiral Ganglion Neurons and Maintenance of Hearing

  • Byeonghyeon Lee
  • Jeong-In Baek
  • Hyehyun Min
  • Seung-Hyun Bae
  • Kyeonghye Moon
  • Min-A Kim
  • Ye-Ri Kim
  • Ben Fogelgren
  • Joshua H. Lipschutz
  • Kyu-Yup Lee
  • Jinwoong BokEmail author
  • Un-Kyung KimEmail author
Article

Abstract

The exocyst, an octameric protein complex consisting of Exoc1 through Exoc8, was first determined to regulate exocytosis by targeting vesicles to the plasma membrane in yeast to mice. In addition to this fundamental role, the exocyst complex has been implicated in other cellular processes. In this study, we investigated the role of the exocyst in cochlear development and hearing by targeting EXOC5, a central exocyst component. Deleting Exoc5 in the otic epithelium with widely used Cre lines resulted in early lethality. Thus, we generated two different inner ear-specific Exoc5 knockout models by crossing Gfi1Cre mice with Exoc5f/f mice for hair cell-specific deletion (Gfi1Cre/+;Exoc5f/f) and by in utero delivery of rAAV-iCre into the otocyst of embryonic day 12.5 for deletion throughout the otic epithelium (rAAV2/1-iCre;Exoc5f/f). Gfi1Cre/+;Exoc5f/f mice showed relatively normal hair cell morphology until postnatal day 20, after which hair cells underwent apoptosis accompanied by disorganization of stereociliary bundles, resulting in progressive hearing loss. rAAV2/1-iCre;Exoc5f/f mice exhibited abnormal neurite morphology, followed by apoptotic degeneration of spiral ganglion neurons (SGNs) and hair cells, which led to profound and early-onset hearing loss. These results demonstrate that Exoc5 is essential for the normal development and survival of cochlear hair cells and SGNs, as well as the functional maintenance of hearing.

Keywords

Exoc5 Exocyst Cochlea Spiral ganglion Hearing loss 

Abbreviations

IHCs

Inner hair cells

SGNs

Spiral ganglion neurons

E

Embryonic day

rAAV

Recombinant adeno-associated virus

rAAV2/1

AAV serotype 2 and a capsid from AAV serotype 1

iCre

Codon-improved Cre recombinase

eGFP

Enhanced green fluorescent protein

GC/mL

Genome copies per milliliter

NGS

Normal goat serum

PBS-Tx

0.1% Triton X-100 in 1× PBS

PFA

Paraformaldehyde

OCT

Optimal cutting temperature compound

H&E

Hematoxylin-eosin

RT

Room temperature

DAPI

4′-6-Diamidino-2-phenylindole

ABR

Auditory brainstem response

P

Postnatal day

TDT

Tucker Davis Technology

SPL

Sound pressure level

SEM

Scanning electron microscopy

RT-PCR

Reverse-transcription polymerase chain reaction

TUNEL

Terminal deoxynucleotidyl transferase dUTP nick end labeling

OHCs

Outer hair cells

JNK

c-Jun N-terminal kinase

TJ

Tight junction

Notes

Acknowledgements

We thank Dr. Lin Gan for Gfi1Cre/+ mice. The UAB P30 Hepatorenal Fibrocystic Disease Core Center is gratefully acknowledged for generating the Exoc5f/f mice. This work was supported by the National Research Foundation of Korea Grant 2014M3A9D5073865 (to J.B. and U.K.K.), 2017R1C1B2009705 (to J.I.B), and 2017R1A2B3009133 (to J.B.), and by the Yonsei University Future-leading Research Initiative (2015-22-0058). This work was also supported in part by grants from the VA (Merit Award I01 BX000820 to J.H.L) and NIH (P30DK074038 to J.H.L) in the USA.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_857_MOESM1_ESM.docx (529 kb)
ESM 1 (DOCX 529 kb)
12035_2017_857_MOESM2_ESM.docx (478 kb)
ESM 2 (DOCX 477 kb)
12035_2017_857_MOESM3_ESM.docx (173 kb)
ESM 3 (DOCX 173 kb)
12035_2017_857_MOESM4_ESM.docx (624 kb)
ESM 4 (DOCX 623 kb)
12035_2017_857_MOESM5_ESM.docx (855 kb)
ESM 5 (DOCX 854 kb)
12035_2017_857_MOESM6_ESM.docx (1.7 mb)
ESM 6 (DOCX 1.69 mb)
12035_2017_857_MOESM7_ESM.docx (645 kb)
ESM 7 (DOCX 644 kb)

References

  1. 1.
    TerBush DR, Maurice T, Roth D, Novick P (1996) The exocyst is a multiprotein complex required for exocytosis in Saccharomyces cerevisiae. EMBO J 15(23):6483–6494CrossRefGoogle Scholar
  2. 2.
    Zajac A, Sun X, Zhang J, Guo W (2005) Cyclical regulation of the exocyst and cell polarity determinants for polarized cell growth. Mol Biol Cell 16(3):1500–1512.  https://doi.org/10.1091/mbc.E04-10-0896 CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Hsu SC, Ting AE, Hazuka CD, Davanger S, Kenny JW, Kee Y, Scheller RH (1996) The mammalian brain rsec6/8 complex. Neuron 17(6):1209–1219.  https://doi.org/10.1016/S0896-6273(00)80251-2 CrossRefPubMedGoogle Scholar
  4. 4.
    Taheri-Talesh N, Horio T, Araujo-Bazan L, Dou X, Espeso EA, Penalva MA, Osmani SA, Oakley BR (2008) The tip growth apparatus of Aspergillus nidulans. Mol Biol Cell 19(4):1439–1449.  https://doi.org/10.1091/mbc.E07-05-0464 CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Wu B, Guo W (2015) The exocyst at a glance. J Cell Sci 128(16):2957–2964.  https://doi.org/10.1242/jcs.156398 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Grindstaff KK, Yeaman C, Anandasabapathy N, Hsu SC, Rodriguez-Boulan E, Scheller RH, Nelson WJ (1998) Sec6/8 complex is recruited to cell-cell contacts and specifies transport vesicle delivery to the basal-lateral membrane in epithelial cells. Cell 93(5):731–740.  https://doi.org/10.1016/S0092-8674(00)81435-X CrossRefPubMedGoogle Scholar
  7. 7.
    Lavy M, Bloch D, Hazak O, Gutman I, Poraty L, Sorek N, Sternberg H, Yalovsky S (2007) A novel ROP/RAC effector links cell polarity, root-meristem maintenance, and vesicle trafficking. Curr Biol 17(11):947–952.  https://doi.org/10.1016/j.cub.2007.04.038 CrossRefPubMedGoogle Scholar
  8. 8.
    Zuo X, Zhang J, Zhang Y, Hsu SC, Zhou D, Guo W (2006) Exo70 interacts with the Arp2/3 complex and regulates cell migration. Nat Cell Biol 8(12):1383–1388.  https://doi.org/10.1038/ncb1505 CrossRefPubMedGoogle Scholar
  9. 9.
    Vega IE, Hsu SC (2001) The exocyst complex associates with microtubules to mediate vesicle targeting and neurite outgrowth. J Neurosci 21(11):3839–3848CrossRefGoogle Scholar
  10. 10.
    Brennwald P (2013) Membrane traffic: the exocyst meets the cell cycle. Curr Biol 23(18):R838–R840.  https://doi.org/10.1016/j.cub.2013.08.007 CrossRefPubMedGoogle Scholar
  11. 11.
    Bodemann BO, Orvedahl A, Cheng T, Ram RR, Ou YH, Formstecher E, Maiti M, Hazelett CC et al (2011) RalB and the exocyst mediate the cellular starvation response by direct activation of autophagosome assembly. Cell 144(2):253–267.  https://doi.org/10.1016/j.cell.2010.12.018 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Zuo X, Guo W, Lipschutz JH (2009) The exocyst protein Sec10 is necessary for primary ciliogenesis and cystogenesis in vitro. Mol Biol Cell 20(10):2522–2529.  https://doi.org/10.1091/mbc.E08-07-0772 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Seixas C, Choi SY, Polgar N, Umberger NL, East MP, Zuo X, Moreiras H, Ghossoub R et al (2016) Arl13b and the exocyst interact synergistically in ciliogenesis. Mol Biol Cell 27(2):308–320.  https://doi.org/10.1091/mbc.E15-02-0061 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Lipschutz JH, Mostov KE (2002) Exocytosis: the many masters of the exocyst. Curr Biol 12(6):R212–R214.  https://doi.org/10.1016/S0960-9822(02)00753-4 CrossRefPubMedGoogle Scholar
  15. 15.
    Zhang X, Orlando K, He B, Xi F, Zhang J, Zajac A, Guo W (2008) Membrane association and functional regulation of Sec3 by phospholipids and Cdc42. J Cell Biol 180(1):145–158.  https://doi.org/10.1083/jcb.200704128 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Zuo X, Fogelgren B, Lipschutz JH (2011) The small GTPase Cdc42 is necessary for primary ciliogenesis in renal tubular epithelial cells. J Biol Chem 286(25):22469–22477.  https://doi.org/10.1074/jbc.M111.238469 CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Fogelgren B, Polgar N, Lui VH, Lee AJ, Tamashiro KK, Napoli JA, Walton CB, Zuo X et al (2015) Urothelial defects from targeted inactivation of exocyst Sec10 in mice cause ureteropelvic junction obstructions. PLoS One 10(6):e0129346.  https://doi.org/10.1371/journal.pone.0129346 CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Choi SY, Chacon-Heszele MF, Huang L, McKenna S, Wilson FP, Zuo X, Lipschutz JH (2013) Cdc42 deficiency causes ciliary abnormalities and cystic kidneys. J Am Soc Nephrol 24(9):1435–1450.  https://doi.org/10.1681/ASN.2012121236 CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Moritz OL, Tam BM, Hurd LL, Peranen J, Deretic D, Papermaster DS (2001) Mutant rab8 impairs docking and fusion of rhodopsin-bearing post-Golgi membranes and causes cell death of transgenic Xenopus rods. Mol Biol Cell 12(8):2341–2351.  https://doi.org/10.1091/mbc.12.8.2341 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Nachury MV, Loktev AV, Zhang Q, Westlake CJ, Peranen J, Merdes A, Slusarski DC, Scheller RH et al (2007) A core complex of BBS proteins cooperates with the GTPase Rab8 to promote ciliary membrane biogenesis. Cell 129(6):1201–1213.  https://doi.org/10.1016/j.cell.2007.03.053 CrossRefPubMedGoogle Scholar
  21. 21.
    Anttonen T, Kirjavainen A, Belevich I, Laos M, Richardson WD, Jokitalo E, Brakebusch C, Pirvola U (2012) Cdc42-dependent structural development of auditory supporting cells is required for wound healing at adulthood. Sci Rep 2(1):978.  https://doi.org/10.1038/srep00978 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Heidrych P, Zimmermann U, Bress A, Pusch CM, Ruth P, Pfister M, Knipper M, Blin N (2008) Rab8b GTPase, a protein transport regulator, is an interacting partner of otoferlin, defective in a human autosomal recessive deafness form. Hum Mol Genet 17(23):3814–3821.  https://doi.org/10.1093/hmg/ddn279 CrossRefPubMedGoogle Scholar
  23. 23.
    Kirjavainen A, Laos M, Anttonen T, Pirvola U (2015) The Rho GTPase Cdc42 regulates hair cell planar polarity and cellular patterning in the developing cochlea. Biol Open 4(4):516–526.  https://doi.org/10.1242/bio.20149753 CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Roux I, Safieddine S, Nouvian R, Grati M, Simmler MC, Bahloul A, Perfettini I, Le Gall M et al (2006) Otoferlin, defective in a human deafness form, is essential for exocytosis at the auditory ribbon synapse. Cell 127(2):277–289.  https://doi.org/10.1016/j.cell.2006.08.040 CrossRefPubMedGoogle Scholar
  25. 25.
    Blake JA, Eppig JT, Kadin JA, Richardson JE, Smith CL, Bult CJ, the Mouse Genome Database G (2017) Mouse Genome Database (MGD)-2017: community knowledge resource for the laboratory mouse. Nucleic Acids Res 45(D1):D723–D729.  https://doi.org/10.1093/nar/gkw1040 CrossRefPubMedGoogle Scholar
  26. 26.
    Guo W, Roth D, Walch-Solimena C, Novick P (1999) The exocyst is an effector for Sec4p, targeting secretory vesicles to sites of exocytosis. EMBO J 18(4):1071–1080.  https://doi.org/10.1093/emboj/18.4.1071 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Seo YJ, Ko SB, Ha TH, Gong TH, Bong JP, Park DJ, Park SY (2015) Association of hearing impairment with chronic kidney disease: a cross-sectional study of the Korean general population. BMC Nephrol 16(1):154.  https://doi.org/10.1186/s12882-015-0151-0 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Lin C, Hsu HT, Lin YS, Weng SF (2013) Increased risk of getting sudden sensorineural hearing loss in patients with chronic kidney disease: a population-based cohort study. Laryngoscope 123(3):767–773.  https://doi.org/10.1002/lary.23669 CrossRefPubMedGoogle Scholar
  29. 29.
    Norgett EE, Golder ZJ, Lorente-Canovas B, Ingham N, Steel KP, Karet Frankl FE (2012) Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype. Proc Natl Acad Sci U S A 109(34):13775–13780.  https://doi.org/10.1073/pnas.1204257109 CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Yang H, Gan J, Xie X, Deng M, Feng L, Chen X, Gao Z, Gan L (2010) Gfi1-Cre knock-in mouse line: A tool for inner ear hair cell-specific gene deletion. Genesis 48(6):400–406.  https://doi.org/10.1002/dvg.20632 CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Kim MA, Cho HJ, Bae SH, Lee B, Oh SK, Kwon TJ, Ryoo ZY, Kim HY et al (2016) Methionine sulfoxide reductase B3-targeted in utero gene therapy rescues hearing function in a mouse model of congenital sensorineural hearing loss. Antioxid Redox Signal 24(11):590–602.  https://doi.org/10.1089/ars.2015.6442 CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Kwon TJ, Oh SK, Kim YR, Kim MA, Lee B, Choi KS, Lee J, Kim UK et al (2014) Methionine sulfoxide reductase A, B1 and B2 are likely to be involved in the protection against oxidative stress in the inner ear. Cells Tissues Organs 199(4):294–300.  https://doi.org/10.1159/000368893 CrossRefPubMedGoogle Scholar
  33. 33.
    Tarchini B, Jolicoeur C, Cayouette M (2013) A molecular blueprint at the apical surface establishes planar asymmetry in cochlear hair cells. Dev Cell 27(1):88–102.  https://doi.org/10.1016/j.devcel.2013.09.011 CrossRefPubMedGoogle Scholar
  34. 34.
    Ohyama T, Groves AK (2004) Generation of Pax2-Cre mice by modification of a Pax2 bacterial artificial chromosome. Genesis 38(4):195–199.  https://doi.org/10.1002/gene.20017 CrossRefPubMedGoogle Scholar
  35. 35.
    Hebert JM, McConnell SK (2000) Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures. Dev Biol 222(2):296–306.  https://doi.org/10.1006/dbio.2000.9732 CrossRefPubMedGoogle Scholar
  36. 36.
    Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, Ng LL, Palmiter RD et al (2010) A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci 13(1):133–140.  https://doi.org/10.1038/nn.2467 CrossRefPubMedGoogle Scholar
  37. 37.
    Shi F, Hu L, Edge AS (2013) Generation of hair cells in neonatal mice by beta-catenin overexpression in Lgr5-positive cochlear progenitors. Proc Natl Acad Sci U S A 110(34):13851–13856.  https://doi.org/10.1073/pnas.1219952110 CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Duncan JS, Fritzsch B (2013) Continued expression of GATA3 is necessary for cochlear neurosensory development. PLoS One 8(4):e62046.  https://doi.org/10.1371/journal.pone.0062046 CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Buret L, Rebillard G, Brun E, Angebault C, Pequignot M, Lenoir M, Do-Cruzeiro M, Tournier E et al (2016) Loss of function of in mice induces deafness and cochlear outer hair cells’ degeneration. Cell Death Discov 2:16017.  https://doi.org/10.1038/cddiscovery.2016.17 CrossRefPubMedPubMedCentralGoogle Scholar
  40. 40.
    Balakireva M, Rosse C, Langevin J, Chien YC, Gho M, Gonzy-Treboul G, Voegeling-Lemaire S, Aresta S et al (2006) The Ral/exocyst effector complex counters c-Jun N-terminal kinase-dependent apoptosis in Drosophila melanogaster. Mol Cell Biol 26(23):8953–8963.  https://doi.org/10.1128/MCB.00506-06 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tanaka T, Kikuchi N, Goto K, Iino M (2016) Sec6/8 regulates Bcl-2 and Mcl-1, but not Bcl-xl, in malignant peripheral nerve sheath tumor cells. Apoptosis 21(5):594–608.  https://doi.org/10.1007/s10495-016-1230-9 CrossRefPubMedGoogle Scholar
  42. 42.
    Polgar N, Lee AJ, Lui VH, Napoli JA, Fogelgren B (2015) The exocyst gene Sec10 regulates renal epithelial monolayer homeostasis and apoptotic sensitivity. Am J Physiol 309(3):C190–C201.  https://doi.org/10.1152/ajpcell.00011.2015 CrossRefGoogle Scholar
  43. 43.
    Ben-Yosef T, Belyantseva IA, Saunders TL, Hughes ED, Kawamoto K, Van Itallie CM, Beyer LA, Halsey K et al (2003) Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Hum Mol Genet 12(16):2049–2061.  https://doi.org/10.1093/hmg/ddg210 CrossRefPubMedGoogle Scholar
  44. 44.
    Nakano Y, Kim SH, Kim HM, Sanneman JD, Zhang Y, Smith RJ, Marcus DC, Wangemann P et al (2009) A claudin-9-based ion permeability barrier is essential for hearing. PLoS Genet 5(8):e1000610.  https://doi.org/10.1371/journal.pgen.1000610 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Kitajiri S, Katsuno T, Sasaki H, Ito J, Furuse M, Tsukita S (2014) Deafness in occludin-deficient mice with dislocation of tricellulin and progressive apoptosis of the hair cells. Biol Open 3(8):759–766.  https://doi.org/10.1242/bio.20147799 CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Nayak G, Lee SI, Yousaf R, Edelmann SE, Trincot C, Van Itallie CM, Sinha GP, Rafeeq M et al (2013) Tricellulin deficiency affects tight junction architecture and cochlear hair cells. J Clin Invest 123(9):4036–4049.  https://doi.org/10.1172/JCI69031 CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Gulley RL, Reese TS (1976) Intercellular junctions in the reticular lamina of the organ of Corti. J Neurocytol 5(4):479–507.  https://doi.org/10.1007/BF01181652 CrossRefPubMedGoogle Scholar
  48. 48.
    Zenner HP, Reuter G, Zimmermann U, Gitter AH, Fermin C, LePage EL (1994) Transitory endolymph leakage induced hearing loss and tinnitus: depolarization, biphasic shortening and loss of electromotility of outer hair cells. Eur Arch Otorhinolaryngol 251(3):143–153CrossRefGoogle Scholar
  49. 49.
    Morozko EL, Nishio A, Ingham NJ, Chandra R, Fitzgerald T, Martelletti E, Borck G, Wilson E et al (2015) ILDR1 null mice, a model of human deafness DFNB42, show structural aberrations of tricellular tight junctions and degeneration of auditory hair cells. Hum Mol Genet 24(3):609–624.  https://doi.org/10.1093/hmg/ddu474 CrossRefPubMedGoogle Scholar
  50. 50.
    Blankenship JT, Fuller MT, Zallen JA (2007) The Drosophila homolog of the Exo84 exocyst subunit promotes apical epithelial identity. J Cell Sci 120(Pt 17):3099–3110.  https://doi.org/10.1242/jcs.004770 CrossRefPubMedGoogle Scholar
  51. 51.
    Hazelett CC, Sheff D, Yeaman C (2011) RalA and RalB differentially regulate development of epithelial tight junctions. Mol Biol Cell 22(24):4787–4800.  https://doi.org/10.1091/mbc.E11-07-0657 CrossRefPubMedPubMedCentralGoogle Scholar
  52. 52.
    Muslin AJ, Tanner JW, Allen PM, Shaw AS (1996) Interaction of 14-3-3 with signaling proteins is mediated by the recognition of phosphoserine. Cell 84(6):889–897.  https://doi.org/10.1016/S0092-8674(00)81067-3 CrossRefPubMedGoogle Scholar
  53. 53.
    Leto D, Uhm M, Williams A, Chen XW, Saltiel AR (2013) Negative regulation of the RalGAP complex by 14-3-3. J Biol Chem 288(13):9272–9283.  https://doi.org/10.1074/jbc.M112.426106 CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Vasara T, Keranen S, Penttila M, Saloheimo M (2002) Characterisation of two 14-3-3 genes from Trichoderma reesei: interactions with yeast secretory pathway components. Biochim Biophys Acta 1590(1–3):27–40.  https://doi.org/10.1016/S0167-4889(02)00197-0 CrossRefPubMedGoogle Scholar
  55. 55.
    Murthy M, Garza D, Scheller RH, Schwarz TL (2003) Mutations in the exocyst component Sec5 disrupt neuronal membrane traffic, but neurotransmitter release persists. Neuron 37(3):433–447.  https://doi.org/10.1016/S0896-6273(03)00031-X CrossRefPubMedGoogle Scholar
  56. 56.
    Hazuka CD, Foletti DL, Hsu SC, Kee Y, Hopf FW, Scheller RH (1999) The sec6/8 complex is located at neurite outgrowth and axonal synapse-assembly domains. J Neurosci 19(4):1324–1334CrossRefGoogle Scholar
  57. 57.
    Lalli G (2009) RalA and the exocyst complex influence neuronal polarity through PAR-3 and aPKC. J Cell Sci 122(Pt 10):1499–1506.  https://doi.org/10.1242/jcs.044339 CrossRefPubMedGoogle Scholar
  58. 58.
    Puel JL, Ruel J, Gervais d'Aldin C, Pujol R (1998) Excitotoxicity and repair of cochlear synapses after noise-trauma induced hearing loss. Neuroreport 9(9):2109–2114.  https://doi.org/10.1097/00001756-199806220-00037 CrossRefPubMedGoogle Scholar
  59. 59.
    Buniello A, Ingham NJ, Lewis MA, Huma AC, Martinez-Vega R, Varela-Nieto I, Vizcay-Barrena G, Fleck RA et al (2016) Wbp2 is required for normal glutamatergic synapses in the cochlea and is crucial for hearing. EMBO Mol Med 8(3):191–207.  https://doi.org/10.15252/emmm.201505523 CrossRefPubMedPubMedCentralGoogle Scholar
  60. 60.
    Kujawa SG, Liberman MC (2009) Adding insult to injury: cochlear nerve degeneration after “temporary” noise-induced hearing loss. J Neurosci 29(45):14077–14085.  https://doi.org/10.1523/JNEUROSCI.2845-09.2009 CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Dulubova I, Khvotchev M, Liu S, Huryeva I, Sudhof TC, Rizo J (2007) Munc18-1 binds directly to the neuronal SNARE complex. Proc Natl Acad Sci U S A 104(8):2697–2702.  https://doi.org/10.1073/pnas.0611318104 CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Morgera F, Sallah MR, Dubuke ML, Gandhi P, Brewer DN, Carr CM, Munson M (2012) Regulation of exocytosis by the exocyst subunit Sec6 and the SM protein Sec1. Mol Biol Cell 23(2):337–346.  https://doi.org/10.1091/mbc.E11-08-0670 CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Seal RP, Akil O, Yi E, Weber CM, Grant L, Yoo J, Clause A, Kandler K et al (2008) Sensorineural deafness and seizures in mice lacking vesicular glutamate transporter 3. Neuron 57(2):263–275.  https://doi.org/10.1016/j.neuron.2007.11.032 CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    Gierut JJ, Jacks TE, Haigis KM (2014) Strategies to achieve conditional gene mutation in mice. Cold Spring Harb Protoc 2014(4):339–349.  https://doi.org/10.1101/pdb.top069807 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Biology, College of Natural SciencesKyungpook National UniversityDaeguRepublic of Korea
  2. 2.School of Life Sciences, BK21 Plus KNU Creative BioResearch GroupKyungpook National UniversityDaeguRepublic of Korea
  3. 3.Department of Aroma-applied IndustryDaegu Haany UniversityGyeongsanRepublic of Korea
  4. 4.Department of MedicineMedical University of South CarolinaCharlestonUSA
  5. 5.Department of AnatomyYonsei University College of MedicineSeoulRepublic of Korea
  6. 6.BK21PLUS Project for Medical ScienceYonsei University College of MedicineSeoulRepublic of Korea
  7. 7.Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of MedicineUniversity of Hawaii at ManoaHonoluluUSA
  8. 8.Department of MedicineRalph H. Johnson Veterans Affairs Medical CenterCharlestonUSA
  9. 9.Department of Otorhinolaryngology-Head and Neck Surgery, School of MedicineKyungpook National UniversityDaeguRepublic of Korea
  10. 10.Department of OtorhinolaryngologyYonsei University College of MedicineSeoulRepublic of Korea

Personalised recommendations