Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells

Takehiko Ueyama; Hirofumi Sakaguchi; Takashi Nakamura; Akihiro Goto; Shigefumi Morioka; Aya Shimizu; Kazuki Nakao; Yoshitaka Hishikawa; Yuzuru Ninoyu; Hidetoshi Kassai; Shiro Suetsugu; Takehiko Koji; Bernd Fritzsch; Shigenobu Yonemura; Yasuo Hisa; Michiyuki Matsuda; Atsu Aiba; Naoaki Saito

doi:10.1242/jcs.143602

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Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells

Journal article

Open access

Peer reviewed

Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells

Takehiko Ueyama, Hirofumi Sakaguchi, Takashi Nakamura, Akihiro Goto, Shigefumi Morioka, Aya Shimizu, Kazuki Nakao, Yoshitaka Hishikawa, Yuzuru Ninoyu, Hidetoshi Kassai, …

Journal of cell science, Vol.127(Pt 9), pp.2040-2052

05/01/2014

DOI: 10.1242/jcs.143602

PMID: 24610943

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Abstract

Cdc42 is a key regulator of dynamic actin organization. However, little is known about how Cdc42-dependent actin regulation influences steady-state actin structures in differentiated epithelia. We employed inner ear hair-cell-specific conditional knockout to analyze the role of Cdc42 in hair cells possessing highly elaborate stable actin protrusions (stereocilia). Hair cells of Atoh1-Cre;Cdc42(flox/flox) mice developed normally but progressively degenerated after maturation, resulting in progressive hearing loss particularly at high frequencies. Cochlear hair cell degeneration was more robust in inner hair cells than in outer hair cells, and began as stereocilia fusion and depletion, accompanied by a thinning and waving circumferential actin belt at apical junctional complexes (AJCs). Adenovirus-encoded GFP-Cdc42 expression in hair cells and fluorescence resonance energy transfer (FRET) imaging of hair cells from transgenic mice expressing a Cdc42-FRET biosensor indicated Cdc42 presence and activation at stereociliary membranes and AJCs in cochlear hair cells. Cdc42-knockdown in MDCK cells produced phenotypes similar to those of Cdc42-deleted hair cells, including abnormal microvilli and disrupted AJCs, and downregulated actin turnover represented by enhanced levels of phosphorylated cofilin. Thus, Cdc42 influenced the maintenance of stable actin structures through elaborate tuning of actin turnover, and maintained function and viability of cochlear hair cells.

Immunohistochemistry

Microscopy, Electron, Transmission

Organ Culture Techniques - methods

Hair Cells, Auditory - metabolism

Humans

Actins - metabolism

cdc42 GTP-Binding Protein - metabolism

Cochlea - cytology

Animals

In Situ Hybridization

Microscopy, Electrochemical, Scanning

Cochlea - metabolism

cdc42 GTP-Binding Protein - genetics

Biosensing Techniques

Dogs

Madin Darby Canine Kidney Cells

Fluorescence Resonance Energy Transfer

Mice

Details

Title: Subtitle: Maintenance of stereocilia and apical junctional complexes by Cdc42 in cochlear hair cells
Creators: Takehiko Ueyama - Laboratory of Molecular Pharmacology, Biosignal Research Center, Kobe University, Kobe 657-8501, Japan
Hirofumi Sakaguchi
Takashi Nakamura
Akihiro Goto
Shigefumi Morioka
Aya Shimizu
Kazuki Nakao
Yoshitaka Hishikawa
Yuzuru Ninoyu
Hidetoshi Kassai
Shiro Suetsugu
Takehiko Koji
Bernd Fritzsch
Shigenobu Yonemura
Yasuo Hisa
Michiyuki Matsuda
Atsu Aiba
Naoaki Saito
Resource Type: Journal article
Publication Details: Journal of cell science, Vol.127(Pt 9), pp.2040-2052
DOI: 10.1242/jcs.143602
PMID: 24610943
NLM abbreviation: J Cell Sci
ISSN: 0021-9533
eISSN: 1477-9137
Publisher: England
Language: English
Date published: 05/01/2014
Academic Unit: Iowa Neuroscience Institute; Biology; Craniofacial Anomalies Research Center
Record Identifier: 9984070304102771

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