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

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A Correction to this article was published on 14 January 2019

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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.

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Change history

  • 14 January 2019

    The original article contains an error for a grant number in the Acknowledgements section.

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

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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.

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Author notes

  1. Byeonghyeon Lee and Jeong-In Baek contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea

    Byeonghyeon Lee, Seung-Hyun Bae, Min-A Kim, Ye-Ri Kim & Un-Kyung Kim

  2. School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea

    Byeonghyeon Lee, Min-A Kim, Ye-Ri Kim & Un-Kyung Kim

  3. Department of Aroma-applied Industry, Daegu Haany University, Gyeongsan, 38610, Republic of Korea

    Jeong-In Baek

  4. Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA

    Jeong-In Baek & Joshua H. Lipschutz

  5. Department of Anatomy, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Hyehyun Min, Kyeonghye Moon & Jinwoong Bok

  6. BK21PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Kyeonghye Moon & Jinwoong Bok

  7. Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, 96813, USA

    Ben Fogelgren

  8. Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA

    Joshua H. Lipschutz

  9. Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea

    Kyu-Yup Lee

  10. Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea

    Jinwoong Bok

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  1. Byeonghyeon Lee
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Correspondence to Jinwoong Bok or Un-Kyung Kim.

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Lee, B., Baek, JI., Min, H. et al. Exocyst Complex Member EXOC5 Is Required for Survival of Hair Cells and Spiral Ganglion Neurons and Maintenance of Hearing. Mol Neurobiol 55, 6518–6532 (2018). https://doi.org/10.1007/s12035-017-0857-z

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  • DOI: https://doi.org/10.1007/s12035-017-0857-z

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