# Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs

> **NIH NIH R01** · JACKSON LABORATORY · 2024 · $689,660

## Abstract

PROJECT SUMMARY/ABSTRACT
Vestibular disorders affect as many as 35% of adults past age 40. Studies of the vestibular inner ear have
yielded important insights into how we process and compensate for head motion including the existence of
parallel channels of information in the afferent nerve. In macular organs, for example, two populations of hair
cells adopt opposite planar orientations of their hair bundles and thus opposite responses to head movements.
This highly conserved bidirectional organization was first described in neuromasts, the lateral line organs
sensing water movements in fish, but the genetic program implementing this reversal during development is
only starting to be deciphered. Consequently, ablation studies to reveal the importance of reversal for
vestibular function have not been possible until recently. Here we propose to address this question by
investigating the consequences of inactivating an orphan G protein coupled receptor (GPCRx), implicated by
our preliminary data in orientation reversal in mouse hair cell epithelia. Based on our preliminary data, we
suggest that mouse GPCRx functions downstream of the transcription factor EMX2 and upstream of the
heterotrimeric G protein Gi to reverse a ground state of polarity established by planar cell polarity proteins.
We will test this hypothesis and also use the GPCRx mutant as an animal model to pinpoint how polarity
reversal shapes macular organ responses and downstream effects on vestibular behaviors. To reach these
goals, we will: 1) Use genetics to determine how GPCRx instructs reversal at the molecular level, solving its
epistatic relationship to EMX2, Gi and planar cell polarity proteins in mice, and use zebrafish to test whether
GPCRx-Gi is a conserved effector pathway for reversal. 2) Use molecular markers, electrophysiology and
calcium imaging to resolve hair cell maturation and function in absence of polarity reversal. 3) Determine how
polarity reversal affects afferents' organization and function, with afferent recordings, as well as overall
vestibular function using behavioral tests. Our coherent body of preliminary evidence ensures the feasibility
and the high interest of the project, and our focus on a virtually unstudied receptor protein guarantees
innovation. The multi-PI team is ideally suited to address complementary questions in both the mouse and
zebrafish acoustico-lateralis systems. We anticipate that this collaborative effort will be decisive towards
solving the mechanism of hair cell orientation reversal, its conservation across vertebrates and its significance
for mammalian vestibular physiology. Thorough understanding of polarity reversal will help interpret and design
treatments for vestibular dysfunctions.

## Key facts

- **NIH application ID:** 10744206
- **Project number:** 5R01DC018304-05
- **Recipient organization:** JACKSON LABORATORY
- **Principal Investigator:** Kathleen E Cullen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $689,660
- **Award type:** 5
- **Project period:** 2019-12-01 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744206

## Citation

> US National Institutes of Health, RePORTER application 10744206, Mechanism and Functional Significance of Polarity Reversal in Mechanosensory Organs (5R01DC018304-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10744206. Licensed CC0.

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