# Significance of Myo7a isoforms in hair cell function

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2022 · $468,533

## Abstract

Project Summary/Abstract
Mutations in
myosin VIIa (MYO7A)
are the most common cause of Usher syndrome type 1.
MYO7A is believed
to be essential for the formation and function of the hair cell mechanotransduction (MET) tip link complex and
the stereocilia ankle link, but its precise function in these complexes is not known.
In preliminary studies, we discovered that the cochlea expresses multiple isoforms of MYO7A. In a genetically
engineered mouse model in which the canonical isoform (Myo7a-C) is specifically deleted (Myo7a-ΔC mouse),
MYO7A expression is severely diminished in inner hair cells (IHCs), and to a lesser degree in apical outer hair
cells (OHCs). In contrast, deletion of the alternative isoform Myo7a-N (Myo7a-ΔN mouse) led to a significant
reduction of MYO7A levels in OHCs, varying in intensity along the tonotopic axis.
Analyses of these models led
to the hypothesis that two major isoforms are expressed in a complementary manner in the cochlea: IHCs
predominantly express the canonical isoform MYO7A-C, and much lower levels of the alternative isoform
MYO7A-N. In OHCs, the two isoforms are expressed in opposing gradients along the tonotopic axis.
This
surprising feature of MYO7A expression gave rise to a novel conceptual framework and experimental tools to
interrogate the functional role of MYO7A in the hair cell in the following three aims:
In Specific Aim (SA) 1, we propose to further investigate the variety of MYO7A isoforms, and their expression
and localization in cochlear hair cells. To this end, we have already generated a mouse model in which one of
the isoforms is genetically tagged, allowing us to determine its cellular and subcellular localization and
characterize the isoform-specific interactome.
In SA2, we will test the functional significance of each MYO7A isoform for hair cell MET and hearing
performance. Preliminary electrophysiological studies show that genetic deletion of the canonical isoform
affects resting open probability and current activation in response to fluid jet stimulation in IHCs, consistent
with a putative role of MYO7A in tensioning the tip link complex.
Finally, we ask why different types of hair cells express distinct isoforms of MYO7A. To address this, in SA3,
we test the hypothesis that the differential expression of MYO7A isoforms serves to tune tip link tension in hair
cells, thereby modulating MET current properties along the tonotopic axis.
This project, through a multi-disciplinary collaboration that enabled the combination of molecular manipulations
in the mouse, electrophysiology, imaging and biochemistry techniques, has the potential to provide critical
insights into the function of an important deafness gene.

## Key facts

- **NIH application ID:** 10466879
- **Project number:** 5R01DC018842-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Jung-Bum Shin
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $468,533
- **Award type:** 5
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10466879

## Citation

> US National Institutes of Health, RePORTER application 10466879, Significance of Myo7a isoforms in hair cell function (5R01DC018842-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10466879. Licensed CC0.

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