# Cellular and molecular mechanisms promoting retinal ganglion cell axonal guidance during optic nerve regeneration

> **NIH NIH K99** · UNIVERSITY OF PENNSYLVANIA · 2021 · $117,909

## Abstract

PROJECT SUMMARY
 Visual information is transmitted from the retina in each eye to the brain through the optic nerve, which is
composed of the axons of retinal ganglion cells (RGCs) and associated glia. Diseases that increase intraocular
pressure and damage the RGC bodies and their axons, such as glaucoma, can ultimately result in irreversible
blindness. After damage to RGC axons, regeneration of the mammalian optic nerve is largely deficient due to
limited RGC axonal regrowth compounded by massive injury induced RGC death. Several RGC intrinsic
signaling pathways are known to increase RGC survival and increase long range axonal growth after injury.
However, enhancing RGC axonal growth often results in axonal misguidance during the initial stages of
regeneration, as axons project inappropriately from the optic tract before and at the optic chiasm. Currently, the
identity of extrinsic cues and mechanisms critical for guiding regenerating RGC axons are not well understood.
In addition, the cellular responses and behaviors of glia, immune and other support cells that localize to the optic
tract, which potentially provide guidance cues to regenerating RGC axons, have not yet been described.
 In contrast to most mammals, zebrafish exhibit a remarkable capacity for regeneration. In taking full
advantage of the zebrafish system, the overall goal of the proposed research here is to use an optic nerve
transection assay developed by the laboratory of Dr. Michael Granato in the optically transparent larval zebrafish,
to identify and characterize mechanisms that promote optic nerve regeneration. Preliminary studies from a
candidate genetic screen conducted using this assay identified mutations in three genes critical for guiding
regenerating RGC axons: lh3, a glycosyltransferase critical for posttranslational collagen modifications,
collagen18a1, a presumptive substrate of Lh3, and wntless, which is required for the secretion of Wnt ligands
into the extracellular space. In all three mutants, regenerating RGC axons extend but fail to cross the optic
chiasm, and instead project along aberrant trajectories, revealing that RGC axonal growth toward and across
the optic chiasm requires critical extrinsic guidance cues during regeneration.
 To define the extrinsic cues and cell-cell interactions that guide RGC axons as they navigate towards the
chiasm during regeneration, I propose to use live cell imaging to characterize RGC axonal and glial cell dynamics
in vivo during the initial stages of optic nerve regeneration. I will also determine the cellular and molecular
mechanisms by which Lh3, Collagen18a1, and Wntless promote correct axonal guidance during optic nerve
regeneration and I will use an unbiased transcriptomics approach to identify additional genes required for this
process. I will complete the mentored K99 phase of this proposal in the Granato lab at the University of
Pennsylvania, a top research university with cutting-edge technologies and excellent men...

## Key facts

- **NIH application ID:** 10191752
- **Project number:** 1K99EY032593-01
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Beth Mee Ra Harvey
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $117,909
- **Award type:** 1
- **Project period:** 2021-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191752

## Citation

> US National Institutes of Health, RePORTER application 10191752, Cellular and molecular mechanisms promoting retinal ganglion cell axonal guidance during optic nerve regeneration (1K99EY032593-01). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10191752. Licensed CC0.

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