Grxcr1 regulates hair bundle morphogenesis and is required for normal mechanoelectrical transduction in mouse cochlear hair cells.

Beatriz Lorente-Cánovas,Karen P Steel,Morag A Lewis,Stuart L Johnson,Stephanie Eckrich,Walter Marcotti,Alexander G Obukhov

doi:10.1371/journal.pone.0261530

Beatriz Lorente-Cánovas, Karen P Steel + Show 5 more

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https://doi.org/10.1371/journal.pone.0261530

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Abstract

Tasmanian devil (tde) mice are deaf and exhibit circling behaviour. Sensory hair cells of mutants show disorganised hair bundles with abnormally thin stereocilia. The origin of this mutation is the insertion of a transgene which disrupts expression of the Grxcr1 (glutaredoxin cysteine rich 1) gene. We report here that Grxcr1 exons and transcript sequences are not affected by the transgene insertion in tde homozygous (tde/tde) mice. Furthermore, 5’RACE PCR experiments showed the presence of two different transcripts of the Grxcr1 gene, expressed in both tde/tde and in wild-type controls. However, quantitative analysis of Grxcr1 transcripts revealed a significantly decreased mRNA level in tde/tde mice. The key stereociliary proteins ESPN, MYO7A, EPS8 and PTPRQ were distributed in hair bundles of homozygous tde mutants in a similar pattern compared with control mice. We found that the abnormal morphology of the stereociliary bundle was associated with a reduction in the size and Ca2+-sensitivity of the mechanoelectrical transducer (MET) current. We propose that GRXCR1 is key for the normal growth of the stereociliary bundle prior to the onset of hearing, and in its absence hair cells are unable to mature into fully functional sensory receptors.

Highlights

Hair cells are specialized sensory receptors responsible for the conversion of mechanical stimuli into electrical signals, which are relayed to the central auditory system via the afferent nerve fibres
Scanning electron microscopy of the organ of Corti at postnatal day 7 (P7) confirmed that the stereocilia of tde homozygous mice were abnormally thin with a flaccid and disorganized appearance in both inner hair cells (IHC) and outer hair cells (OHC) compared to control heterozygous (+/tde) mice (Fig 1)
We have shown that GRXCR1 is crucial for the growth of the stereociliary bundles in cochlear hair cells, and is required for the functional maturation of these cells into sensory receptors

Summary

Introduction

Hair cells are specialized sensory receptors responsible for the conversion of mechanical stimuli into electrical signals, which are relayed to the central auditory system via the afferent nerve fibres. Hair bundles protrude from their apical surfaces. The hair bundle is composed of rows of microvilli-like elements called stereocilia, which are graded in height to form a staircase-like structure [1]. Mechanoelectrical transduction occurs when mechanically-gated ion channels, located at the tips of the stereocilia, open in response to sound induced movement of the hair bundle. Stereocilia are composed of a rigid paracrystalline array of parallel, uniformly polarized and regularly cross-linked actin filaments [2].

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