# Effectors of Hedgehog Signaling in the Etiology of Coloboma

> **NIH NIH F31** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2020 · $32,040

## Abstract

Project Summary
Developmental defects in eye structure commonly account for visual impairment in newborns.
One such defect, uveal coloboma, is caused by failed development of the optic fissure and is a
significant cause of pediatric blindness worldwide. One pathway central to this process is the
Hedgehog (Hh) signaling pathway: loss-of-function mutations in the Hh receptor ptch2, which
produce overactive Hh signaling, can result in coloboma. In our recent publication (Gordon and
Lusk et al., 2018), using zebrafish, we determined the cellular basis of normal optic fissure
formation, and identified specific defects in optic fissure and stalk formation in ptch2 mutants, by
utilizing timelapse imaging, 4-dimensional cell tracking, and quantitative analysis of individual
cell behaviors. We determined through transplantation experiments that both cell-intrinsic and
intercellular signaling molecules are involved in the ptch2 mutant phenotype and that this occurs
through a Gli-dependent mechanism. I hypothesize that overactivation of Hh signaling results in
the upregulation of transcriptional targets that directly disrupt cell movements and
morphogenesis, leading to coloboma. The goal of the work proposed here is to identify these
targets and dissect their role in the etiology of coloboma. I propose to use a targeted candidate
approach in parallel with an unbiased sequencing approach in an effort to identify factors
responsible for the ptch2 mutant coloboma phenotype. Based on my preliminary data, I am
investigating Netrin as a cell-extrinsic downstream effector of Hh signaling. In Aim 1, I will
dissect the genetic interaction between Netrin and Hedgehog signaling during optic fissure and
stalk formation, using gain- and loss-of-function approaches. Because I hypothesize at least one
intrinsically-acting molecule downstream of Hh signaling is involved in causing coloboma, in Aim
2, I will use unbiased single-cell RNA-sequencing and functional analysis to identify Hh
downstream genes that are responsible for the ptch2 mutant phenotype. I will identify specific
transcriptomes from cells responding to overactive Hh signaling and directly test the role of
upregulated genes in optic fissure and stalk formation. The work proposed here will allow me to
uncover molecular pathways and potentially novel therapeutic targets regulating formation of the
optic fissure and stalk, with the ultimate goal being a mechanistic understanding of coloboma.

## Key facts

- **NIH application ID:** 10020181
- **Project number:** 5F31EY030758-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sarah Lusk
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $32,040
- **Award type:** 5
- **Project period:** 2019-09-01 → 2022-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10020181

## Citation

> US National Institutes of Health, RePORTER application 10020181, Effectors of Hedgehog Signaling in the Etiology of Coloboma (5F31EY030758-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10020181. Licensed CC0.

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