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Mol Neurobiol. 2018 Aug;55(8):6518-6532. doi: 10.1007/s12035-017-0857-z. Epub 2018 Jan 11.

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

Lee B1,2, Baek JI3,4, Min H5, Bae SH1, Moon K5,6, Kim MA1,2, Kim YR1,2, Fogelgren B7, Lipschutz JH4,8, Lee KY9, Bok J10,11,12, Kim UK13,14.

Author information

1
Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea.
2
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea.
3
Department of Aroma-applied Industry, Daegu Haany University, Gyeongsan, 38610, Republic of Korea.
4
Department of Medicine, Medical University of South Carolina, Charleston, SC, 29425, USA.
5
Department of Anatomy, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
6
BK21PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea.
7
Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI, 96813, USA.
8
Department of Medicine, Ralph H. Johnson Veterans Affairs Medical Center, Charleston, SC, 29401, USA.
9
Department of Otorhinolaryngology-Head and Neck Surgery, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.
10
Department of Anatomy, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. bokj@yuhs.ac.
11
BK21PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. bokj@yuhs.ac.
12
Department of Otorhinolaryngology, Yonsei University College of Medicine, Seoul, 03722, Republic of Korea. bokj@yuhs.ac.
13
Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, 41566, Republic of Korea. kimuk@knu.ac.kr.
14
School of Life Sciences, BK21 Plus KNU Creative BioResearch Group, Kyungpook National University, Daegu, 41566, Republic of Korea. kimuk@knu.ac.kr.

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:

Cochlea; Exoc5; Exocyst; Hearing loss; Spiral ganglion

PMID:
29327200
DOI:
10.1007/s12035-017-0857-z

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