# Mechanisms of Tip Link Tensioning in Mammalian Auditory Hair Cells

> **NIH NIH F31** · UNIVERSITY OF KENTUCKY · 2024 · $43,038

## Abstract

Project Summary
Mammalian auditory hair cells detect sound through deflections of stereocilia that are organized in precise
staircase-like bundles and interconnected by extracellular tip links. Sound-induced deflections modulate the
tension of tip links and convey these forces to mechano-electrical transduction (MET) channels located at
the tips of the shorter rows of stereocilia. Even at rest, there is a certain amount of tension on the tip links,
which ensures detection of the softest sounds and results in some resting amount of MET current
continuously entering the cell. We and other groups demonstrated that this resting MET current regulates
the height of transducing stereocilia, thereby providing a plausible mechanism for long-term maintenance of
the shape of stereocilia bundle. Furthermore, my recent study revealed that MET-dependent retraction of
stereocilia in mammalian auditory hair cells increases the tension within MET machinery, which could only
occur if, in contrast to the classical models, the upper end of the tip link is not freely moved by myosin
motors but instead somehow locked to the stereocilia core (Dragich et. al., in review). The proposed project
will explore a potential molecular mechanism of this phenomenon. We hypothesize that Gα-Interacting
Protein, C-terminus-3 (GIPC3) is involved in locking the upper end of the tip link to the stereocilia actin core.
Several mutations in GIPC3 have been linked to hearing loss in humans, but the exact function of this
protein in the mammalian cochlea is yet unknown. Data from our collaborator (Dr. Craig Vander Kooi) show
that GIPC3 interacts with myosin VI (MYO6) and the upper tip link density (UTLD) proteins, cadherin-23
(CDH23) and potentially myosin VIIa (MYO7a). My preliminary data also show that GIPC3 deficiency results
in the loss of resting MET current and “slipping adaptation” of the MET responses in cochlear outer hair
cells of mice carrying the p.W301X mutation in Gipc3, recapitulating a known human deafness. In this
project, we will use this Gipc3W301X mouse strain as well as a Gipc3 knockout strain to determine: (a) the
role of GIPC3 in regulating the tension within the MET machinery and adaptation in mammalian auditory
hair cells; (b) the role of GIPC3 in UTLD assembly and maintenance; and (c) the potential for restoring
wildtype MET responses in Gipc3-deficient mice. This project will not only identify the specific role of GIPC3
in mammalian auditory hair cells but also elucidate the mechanisms behind the maintenance of stereocilia
bundle structure and tensioning of the MET machinery. Approaching this project using electrophysiology,
advanced electron microscopy, and cell biology techniques will help me to develop a unique set of scientific
skills in preparation for a career as a future principal investigator in basic auditory research.

## Key facts

- **NIH application ID:** 10865144
- **Project number:** 5F31DC020639-03
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Abigail Dragich
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,038
- **Award type:** 5
- **Project period:** 2022-07-31 → 2026-07-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10865144

## Citation

> US National Institutes of Health, RePORTER application 10865144, Mechanisms of Tip Link Tensioning in Mammalian Auditory Hair Cells (5F31DC020639-03). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10865144. Licensed CC0.

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