# Understanding the Role of GARP Proteins in Rod Outer Segment Disc Formation and Retinal Degeneration

> **NIH NIH F32** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $81,592

## Abstract

PROJECT SUMMARY
Human vision begins in the retina where light capture stimulates an electrical signal within the outer
segment organelle of photoreceptor neurons. The outer segment is a modified primary cilium built with
hundreds of flattened membranous discs that maximize the light-absorbing surface. Phototoxicity
damages the disc membranes requiring that the outer segment be continuously renewed through the
addition of new discs at the base. Outer segment length is maintained by phagocytosis of old discs
from the distal tip by the adjacent retinal pigment epithelial cells. The unique architecture of the outer
segment compartment is critical to photoreceptor health and mutations that disrupt disc stacks underly
many forms of human retinal degeneration. The purpose of this proposal is to investigate components
that contribute to forming and maintaining discs in order to better understand the pathogenesis of
inherited retinal degeneration.
 Rod photoreceptors express three proteins containing the glutamic acid rich protein (GARP)
domain: the β1-subunit of the cyclic nucleotide-gated channel (CNG), GARP1, and GARP2. In mice,
genetic ablation of all three GARP proteins results in extraneous membrane outgrowth from the outer
segment base, a hallmark of defects in disc synthesis. I have new preliminary data indicating that the
key disc morphogenesis protein, protocadherin 21 (PCDH21), is dysregulated in this model. These data
led to my hypothesis that GARP proteins help to recruit PCHD21 to the leading edge of the budding
nascent discs and the loss of GARP proteins results in reduced rates of disc growth that contributes to
retinal degeneration. I have further identified that the CNGβ1 subunit is necessary to stabilize PCDH21
at the outer segment base, making it the primary focus of Aim 1. I will confirm that loss of PCDH21 from
the outer segment base drives defects in disc morphogenesis and test whether CNGβ1 is sufficient to
regulate PCDH21 and disc formation.
 Recent insights into the molecular mechanisms underlying disc formation have revealed the urgent
need to quantitatively measure rates of disc synthesis, yet the tools to do so lack sensitivity and
versatility. As a solution, I developed an inducible mouse model that expresses a photoconvertible,
outer segment targeted, transmembrane reporter that I will use to quantify new disc addition. In Aim 2, I
will characterize this novel mouse model followed by a quantitative comparison of rates of disc growth
between wildtype, GARPKO, and CNGβ1-KO mouse rods to understand how dysregulated disc
formation contributes to retinal degeneration. Completion of these aims will provide mechanistic insight
into the role GARP proteins play in disc formation and outer segment growth kinetics as well as provide
a quantitative tool for future investigation of disc renewal in health and disease.

## Key facts

- **NIH application ID:** 10908297
- **Project number:** 5F32EY034760-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Molly Naylor
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $81,592
- **Award type:** 5
- **Project period:** 2023-08-26 → 2026-08-25

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908297

## Citation

> US National Institutes of Health, RePORTER application 10908297, Understanding the Role of GARP Proteins in Rod Outer Segment Disc Formation and Retinal Degeneration (5F32EY034760-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10908297. Licensed CC0.

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