# Molecular mechanisms of photoreceptor outer segment morphogenesis

> **NIH NIH R01** · DUKE UNIVERSITY · 2021 · $430,862

## Abstract

This proposal addresses one of the most fundamental unsolved problems in vision: the molecular and cellular
mechanism responsible for building and maintaining the light-sensitive organelle of vertebrate photoreceptor cells,
the outer segment. The outer segment is a ciliary structure filled with a stack of disc membranes, which provide
vast surfaces for light capture and harbor proteins comprising the phototransduction machinery. Discs are renewed
on a daily basis in order to counteract the adverse effects of light exposure, and the fidelity of disc renewal is critical
for maintaining photoreceptor health and normal vision. Previous studies established that photoreceptor discs are
formed as serial evaginations of the plasma membrane at the outer segment base. Yet, the molecular mechanisms
responsible for performing these membrane transformations remain poorly understood. The research strategy
outlined in this proposal is built upon the recently uncovered analogy between disc formation in photoreceptor cells
and a fundamental property of many other cilia types - the ability to release small extraciliary vesicles, called
ectosomes. The photoreceptor cilium also has an innate ability to release massive amounts of ectosomes.
However, in normal photoreceptors this process is suppressed by the disc-specific protein, peripherin-2, which
retains the budding membranes at the outer segment base, thereby enabling them to be morphed into discs.
The formation of both ciliary ectosomes and photoreceptor discs requires the action of the actin cytoskeleton,
and recent evidence suggests that ectosome release also relies on the ESCRT protein complex. Therefore, Aim
1 will explore whether a similar interplay between the actin cytoskeleton and ESCRT proteins is responsible for
performing the first steps of photoreceptor disc formation. Aim 2 will explore the mechanism by which
peripherin-2 transforms the functional state of the photoreceptor cilium from releasing ectosomes to retaining
membranes at the outer segment base and transforming them into discs. Elucidating these mechanisms is critical
for advancing our understanding of basic photoreceptor cell biology and pathobiological mechanisms underlying
photoreceptor degeneration frequently associated with defects in outer segment morphogenesis.

## Key facts

- **NIH application ID:** 10171854
- **Project number:** 5R01EY012859-23
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Vadim Y Arshavsky
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $430,862
- **Award type:** 5
- **Project period:** 2000-02-07 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171854

## Citation

> US National Institutes of Health, RePORTER application 10171854, Molecular mechanisms of photoreceptor outer segment morphogenesis (5R01EY012859-23). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10171854. Licensed CC0.

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