# Investigating Photoreceptor Nuclear Migration Defects Caused by Loss of Retinitis Pigmentosa 2.

> **NIH NIH R01** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2024 · $496,661

## Abstract

ABSTRACT
Retinal inherited diseases are a leading cause of blindness worldwide. Despite major progress in the discovery
of causative genes underlying inherited retinal disease, understanding the natural history and phenotype of a
particular molecular diagnosis remains limited. Recently, we found that dominant human mutations in ARL3
cause higher levels of Arl3-GTP activity, resulting in a developmental phenotype that prevents photoreceptor
nuclei from translocating properly into the outer nuclear layer of the retina. Arl3 is a small GTPase that regulates
the enrichment of lipid proteins into the cilium. Building from this discovery, we wanted to determine whether
other mutations that cause elevated levels of Arl3-GTP activity had a similar phenotype. RP2 is the GTPase
activating protein (GAP) that facilitates GTP hydrolysis by returning Arl3 returning it to the inactive GDP state.
Human mutations in the RP2 gene cause X-linked retinitis pigmentosa and loss of RP2 GAP activity would be
expected to increase levels of Arl3-GTP in the cell. In our preliminary data, we rederived the RP2null mouse and
found that it has the same photoreceptor nuclear migration defect as we observed with dominant human
mutations in ARL3. The mislocalization of photoreceptor nuclei into the inner nuclear layer was overlooked in
previous publications and demands a thorough examination. The goals of our proposal are to investigate how
this developmental phenotype affects photoreceptor function and/or health, whether this phenotype can be
restored by sequestering the overly active Arl3-GTP and identify the ciliary signal regulating nuclear migration
that is perturbed by excess Arl3-GTP activity. In addition to building a comprehensive understanding of how
mislocalized photoreceptor nuclei affect function and lead to retinal degeneration, our aims utilize proximity
labeling approaches to uncover the ciliary signal and the mechanism by which photoreceptors guide nuclear
migration during development. Furthermore, we will employ gene delivery techniques in the RP2null rods to rapidly
screen candidates that we previously found restored the migration defect caused by dominant ARL3 mutations.
Completing our aims will provide insight into post-mitotic nuclear migration within the developing retina, how
these processes fail during disease, and how mislocalized photoreceptor nuclei impact retinal health and
function. This proposal will provide fundamental knowledge about the pathobiology underlying RP2 and ARL3
gene mutations and identify potential therapeutic targets for patients suffering from inherited blindness.

## Key facts

- **NIH application ID:** 10854338
- **Project number:** 1R01EY036019-01
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Jillian Nydam Pearring
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $496,661
- **Award type:** 1
- **Project period:** 2024-07-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10854338

## Citation

> US National Institutes of Health, RePORTER application 10854338, Investigating Photoreceptor Nuclear Migration Defects Caused by Loss of Retinitis Pigmentosa 2. (1R01EY036019-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10854338. Licensed CC0.

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