Grxcr2 is required for stereocilia morphogenesis in the cochlea

Matthew R Avenarius; Jae-Yun Jung; Charles Askew; Sherri M Jones; Kristina L Hunker; Hela Azaiez; Atteeq U Rehman; Margit Schraders; Hossein Najmabadi; Hannie Kremer; Richard J H Smith; Gwenaëlle S G Géléoc; David F Dolan; Yehoash Raphael; David C Kohrman

doi:10.1371/journal.pone.0201713

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Grxcr2 is required for stereocilia morphogenesis in the cochlea

Journal article

Open access

Peer reviewed

Grxcr2 is required for stereocilia morphogenesis in the cochlea

Matthew R Avenarius, Jae-Yun Jung, Charles Askew, Sherri M Jones, Kristina L Hunker, Hela Azaiez, Atteeq U Rehman, Margit Schraders, Hossein Najmabadi, Hannie Kremer, …

PloS one, Vol.13(8), pp.e0201713-e0201713

2018

DOI: 10.1371/journal.pone.0201713

PMCID: PMC6114524

PMID: 30157177

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Abstract

Hearing and balance depend upon the precise morphogenesis and mechanosensory function of stereocilia, the specialized structures on the apical surface of sensory hair cells in the inner ear. Previous studies of Grxcr1 mutant mice indicated a critical role for this gene in control of stereocilia dimensions during development. In this study, we analyzed expression of the paralog Grxcr2 in the mouse and evaluated auditory and vestibular function of strains carrying targeted mutations of the gene. Peak expression of Grxcr2 occurs during early postnatal development of the inner ear and GRXCR2 is localized to stereocilia in both the cochlea and in vestibular organs. Homozygous Grxcr2 deletion mutants exhibit significant hearing loss by 3 weeks of age that is associated with developmental defects in stereocilia bundle orientation and organization. Despite these bundle defects, the mechanotransduction apparatus assembles in relatively normal fashion as determined by whole cell electrophysiological evaluation and FM1-43 uptake. Although Grxcr2 mutants do not exhibit overt vestibular dysfunction, evaluation of vestibular evoked potentials revealed subtle defects of the mutants in response to linear accelerations. In addition, reduced Grxcr2 expression in a hypomorphic mutant strain is associated with progressive hearing loss and bundle defects. The stereocilia localization of GRXCR2, together with the bundle pathologies observed in the mutants, indicate that GRXCR2 plays an intrinsic role in bundle orientation, organization, and sensory function in the inner ear during development and at maturity.

Amino Acid Sequence

Glutaredoxins - metabolism

Species Specificity

Humans

Genetic Loci - genetics

Cochlea - growth & development

Models, Molecular

Cochlea - cytology

Hearing Loss - pathology

Hearing Loss - genetics

Morphogenesis

Mechanotransduction, Cellular

Animals

Gene Expression Regulation, Developmental

Glutaredoxins - chemistry

Stereocilia - metabolism

Glutaredoxins - genetics

Protein Conformation

Mice

Mutation

Details

Title: Subtitle: Grxcr2 is required for stereocilia morphogenesis in the cochlea
Creators: Matthew R Avenarius - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
Jae-Yun Jung - Department of Otolaryngology/Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
Charles Askew - Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
Sherri M Jones - Department of Communication Sciences and Disorders, East Carolina University, Greenville, North Carolina, United States of America
Kristina L Hunker - Department of Otolaryngology/Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
Hela Azaiez - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Atteeq U Rehman - Section on Human Genetics, Laboratory of Molecular Genetics, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Rockville, Maryland, United States of America
Margit Schraders - Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Hossein Najmabadi - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
Hannie Kremer - Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
Richard J H Smith - Molecular Otolaryngology and Renal Research Laboratories, Carver College of Medicine, University of Iowa, Iowa City, Iowa, United States of America
Gwenaëlle S G Géléoc - Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America
David F Dolan - Department of Otolaryngology/Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
Yehoash Raphael - Department of Otolaryngology/Kresge Hearing Research Institute, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
David C Kohrman - Department of Human Genetics, University of Michigan Medical School, Ann Arbor, Michigan, United States of America
Resource Type: Journal article
Publication Details: PloS one, Vol.13(8), pp.e0201713-e0201713
DOI: 10.1371/journal.pone.0201713
PMID: 30157177
PMCID: PMC6114524
NLM abbreviation: PLoS One
ISSN: 1932-6203
eISSN: 1932-6203
Publisher: Public Library of Science; United States
Grant note: R01 DC006443 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS T32 DC000011 / NIDCD NIH HHS R01 DC008853 / NIDCD NIH HHS R01 DC003049 / NIDCD NIH HHS P30 DC005188 / NIDCD NIH HHS
Language: English
Date published: 2018
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine
Record Identifier: 9984006461502771

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