# Impact of a DFNA20 Gamma Actin Mutation on Mechanotransduction-Dependent Stereocilia Remodeling

> **NIH NIH R01** · UNIVERSITY OF KENTUCKY · 2024 · $76,142

## Abstract

PROJECT SUMMARY/ABSTRACT
 Inner ear hair cells have actin-filled projections known as stereocilia on the apical surface. These
stereocilia are microvilli-like structures that are arranged in highly organized rows of increasing heights
known as “hair bundles”. The stereocilia possess mechano-electrical transduction (MET) channels at
their tips where sound-induced vibration and head motion are converted into electrical signals.
Previously, Velez-Ortega et al. (Elife, 2017) demonstrated that the actin cytoskeleton in stereocilia
exhibits MET-dependent remodeling as the stability of the stereocilia was crucially affected by alterations
to the constant entry of calcium through MET channels (which are partially open at rest). The actin
cytoskeleton within stereocilia is comprised of two actin isoforms, beta and gamma, which are produced
by two separate genes. Prior studies have elucidated that although hair cells can develop hair bundles
in the absence of either actin isoform, these bundles quickly degenerate resulting in hearing loss (Perrin
et al., PLoS Genet, 2010). Thus, it is apparent that both actin isoforms are required for proper stereocilia
stability and maintenance. Here, we hypothesize that a specific mutation in the gamma actin gene leads
to progressive hearing loss (in both human and mouse models) through the exaggeration of MET-
dependent remodeling of the aforementioned actin cytoskeleton. To investigate this hypothesis, Aim 1
will analyze MET-dependent changes to the morphology of stereocilia through scanning electron
microscopy after exposing gamma actin mutant mice and littermate controls to MET channel blockers or
an increase in intracellular calcium buffering. Given that beta and gamma actin exhibit different rates of
polymerization and depolymerization in the presence of calcium (Bergeron et al., J Biol Chem, 2010),
Aim 2 will evaluate how MET-dependent alterations affect the ratio of the beta and gamma actin isoforms
in both the stereocilia and cuticular plate of auditory hair cells in mutant mice and littermate controls using
immunohistochemistry and high-resolution confocal microscopy. Overall, results from this supplement
may elucidate the molecular mechanism that triggers stereocilia degeneration in sensorineural
progressive hearing loss when a mutation in the gamma actin gene is present.

## Key facts

- **NIH application ID:** 11087895
- **Project number:** 3R01DC021325-02S1
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Alejandra Catalina Velez Ortega
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $76,142
- **Award type:** 3
- **Project period:** 2023-06-07 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11087895

## Citation

> US National Institutes of Health, RePORTER application 11087895, Impact of a DFNA20 Gamma Actin Mutation on Mechanotransduction-Dependent Stereocilia Remodeling (3R01DC021325-02S1). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/11087895. Licensed CC0.

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